Inhibitors of histone deacetylase

ABSTRACT

This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for compounds of formula (I) wherein Q, J, L and Z are as defined in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application60/884,287, filed Jan. 10, 2007, and U.S. provisional application60/863,347, filed Oct. 28, 2006.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds for the inhibition of histonedeacetylase.

2. Description of Related Art

In eukaryotic cells, nuclear DNA associates with histones to form acompact complex called chromatin. The histones constitute a family ofbasic proteins which are generally highly conserved across eukaryoticspecies. The core histones, termed H2A, H2B, H3, and H4, associate toform a protein core. DNA winds around this protein core, with the basicamino acids of the histones interacting with the negatively chargedphosphate groups of the DNA. Approximately 146 base pairs of DNA wraparound a histone core to make up a nucleosome particle, the repeatingstructural motif of chromatin.

Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones aresubject to posttranslational acetylation of the N-terminal lysineresidues, a reaction that is catalyzed by histone acetyl transferase(HAT1). Acetylation neutralizes the positive charge of the lysine sidechain, and is thought to impact chromatin structure. Indeed, Taunton etal., Science, 272: 408-411 (1996), teaches that access of transcriptionfactors to chromatin templates is enhanced by histone hyperacetylation.Taunton et al. further teaches that an enrichment in underacetylatedhistone H4 has been found in transcriptionally silent regions of thegenome.

Histone acetylation is a reversible modification, with deacetylationbeing catalyzed by a family of enzymes termed histone deacetylases(HDACs). The molecular cloning of gene sequences encoding proteins withHDAC activity has established the existence of a set of discrete HDACenzyme isoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA,96:4868-4873 (1999), teaches that HDACs may be divided into two classes,the first represented by yeast Rpd3-like proteins, and the secondrepresented by yeast Hd1-like proteins. Grozinger et al. also teachesthat the human HDAC-1, HDAC-2, and HDAC-3 proteins are members of thefirst class of HDACs, and discloses new proteins, named HDAC-4, HDAC-5,and HDAC-6, which are members of the second class of HDACs. Kao et al.,Gene & Development 14:55-66 (2000), discloses an additional member ofthis second class, called HDAC-7. More recently, Hu, E. et al. J. Bio.Chem. 275:15254-13264 (2000) disclosed another member of the first classof histone deacetylases, HDAC-8. Zhou et al., Proc. Natl. Acad. Sci.U.S.A., 98: 10572-10577 (2001) teaches the cloning and characterizationof a new histone deacetylase, HDAC-9. Kao et al., J. Biol. Chem.,277:187-93 (2002) teaches the isolation and characterization ofmammalian HDAC10, a novel histone deacetylase. Gao et al, J. Biol. Chem.(In press) teaches the cloning and functional characterization ofHDAC11, a novel member of the human histone deacetylase family. Shore,Proc. Natl. Acad. Sci. U.S.A. 97: 14030-2 (2000) discloses another classof deacetylase activity, the Sir2 protein family. It has been unclearwhat roles these individual HDAC enzymes play.

Studies utilizing known HDAC inhibitors have established a link betweenacetylation and gene expression. Numerous studies have examined therelationship between HDAC and gene expression. Taunton et al., Science272:408-411 (1996), discloses a human HDAC that is related to a yeasttranscriptional regulator. Cress et al., J. Cell Phys. 184: 1-16 (2000),discloses that, in the context of human cancer, the role of HDAC is as acorepressor of transcription. Ng et al, TIBS 25: March (2000), disclosesHDAC as a pervasive feature of transcriptional repressor systems.Magnaghi-Jaulin et al., Prog. Cell Cycle Res. 4:41-47 (2000), disclosesHDAC as a transcriptional co-regulator important for cell cycleprogression.

Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998),discloses that HDAC activity is inhibited by trichostatin A (TSA), anatural product isolated from Streptomyces hygroscopicus, which has beenshown to inhibit histone deacetylase activity and arrest cell cycleprogression in cells in the G1 and G2 phases (Yoshida et al., J. Biol.Chem. 265: 17174-17179, 1990; Yoshida et al., Exp. Cell Res. 177:122-131, 1988), and by a synthetic compound, suberoylanilide hydroxamicacid (SAHA). Yoshida and Beppu, Exper. Cell Res., 177: 122-131 (1988),teaches that TSA causes arrest of rat fibroblasts at the G₁ and G₂phases of the cell cycle, implicating HDAC in cell cycle regulation.Indeed, Finnin et al., Nature, 401: 188-193 (1999), teaches that TSA andSAHA inhibit cell growth, induce terminal differentiation, and preventthe formation of tumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905,EP 0847992 and JP 258863/96, disclose benzamide derivatives that inducecell differentiation and inhibit HDAC. Delorme et al., WO 01/38322 andWO 2001/070675, disclose additional compounds that serve as HDACinhibitors. Other inhibitors of histone deacetylase activity, includingtrapoxin, depudecin, FR901228 (Fujisawa Pharmaceuticals), and butyrate,have been found to similarly inhibit cell cycle progression in cells(Taunton et al., Science 272: 408-411, 1996; Kijima et al., J. Biol.Chem. 268(30):22429-22435, 1993; Kwon et al., Proc. Natl. Acad. Sci. USA95(7):3356-61, 1998).

Research in the past decade has uncovered a new classification ofinherited neurodegenerative diseases, the polyglutamine (polyQ)expansion diseases. In each, the underlying mutation is an expansion ofa CAG trinucleotide repeat that encodes polyQ in the respective diseaseprotein. All are progressive, ultimately fatal disorders that typicallybegin in adulthood and progress over 10 to 30 years. The clinicalfeatures and pattern of neuronal degeneration differ among the diseases,yet increasing evidence suggests that polyQ diseases share importantpathogenic features. In particular, abnormal protein conformationspromoted by polyQ expansion seem to be central to pathogenesis. Thisclass of PolyQ expansion neurodegenerative disease are Huntington'sDisease (HD), Dentatorubralpallidoluysian atrophy (DRPLA), spinal andbulbar muscular atrophy (SBMA), and five spinocerebellar ataxias (SCA1,SCA2, SCA3/MJD (Machado-Joseph Disease), SCA6 and SCA7).

It is known that certain HDAC inhibitors, for example SAHA, CBHA andpryoxiamide can cross the blood brain barrier at sufficient amounts tosignificantly inhibit HDAC activity causing the accumulation ofacetylated histones in the brain (WO 03/032921). This discoverytherefore provides for the use of HDAC inhibitors for inhibiting HDAC inthe brain, for the treatment of polyglutamine (polyQ) expansiondiseases.

The art provides data that HDAC inhibitors are promising noveltherapeutics for polyglutamine expansion diseases. Other data support atherapeutic benefit of HDAC inhibitors for Huntington's disease.Sadri-Vakili and Cha (Nature Clinical Practice Neurology, 2006,2(6):330-338), and references cited therein, for example, review thecurrent state of knowledge regarding the status of histones inHuntington's Disease and teach that recent studies have shown atherapeutic role for hisone deacetylase inhibitors in a number ofHuntington's Disease models. In vivo, HDAC inhibitors arrest ongoingprogressive neuronal degeneration induced by polygluatmine repeatexpansion, and they reduce lethality in two Drosophila models ofpolyglutamine disease (Steffan et al., 2001, Nautre 413: 739-743).Similar findings were observed with sodium butyrate and TSA (Zhao etal., 2005, J. Expt. Biol., 208:697-705). Gardian et al. (2005, J. Biol.Chem., 280:556-563) showed that phenylbutyrate is capable of improvingsurvival and attenuating brain atrophy in the N171-82Q transgenic mousemodel of Huntington's Disease. In the R6/2 model of Huntington'sDisease, sodium butyrate extended survival, improved motor deficits anddelayed neuropathological sequelae (Ferrante et al., 2003, J. Neurosci.,23:9418-9427). In that same model, suberoylanilide hydroxamic acid(SAHA) was also active in improving the motor impairment (Hockly, 2003,Proc. Natl. Acad. Sci. USA, 100:2041-0246). Ying et al. (2005, J. Biol.Chem., 281:12580-12586) showed that sodium butyrate improved life spanand motor deficits in a mouse model for DRPLA. Bates et al. (2006, TheJournal of Neuroscience, 26(10):2830-2838) reported that inCaenorhabditis elegans expressing a human huntingtin fragment with anexpanded polyglutamine tract (Htn-Q150), knockdown of C. elegans hda-3suppressed Htn-Q150 toxicity. Neuronal expression of hda-3 restoredHtn-Q150 toxicity and suggested that C. elegans HDAC3 acts withinneurons to promote degeneration in response to Htn-Q150.

These findings suggest that inhibition of HDAC activity represents anovel approach for intervening in cell cycle regulation and that HDACinhibitors have great therapeutic potential in the treatment ofpolyglutamine (polyQ) expansion diseases, such as Huntington's Disease.It would be highly desirable to have novel inhibitors of histonedeacetylase.

SUMMARY OF THE INVENTION

The present invention provides compounds for the inhibition of histonedeacetylase.

In a first aspect, the present invention provides compounds that areuseful as inhibitors of histone deacetylase that have the formula (I)and racemic mixtures, diastereomers and enantiomers thereof andN-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof,

wherein

Q, J, L and Z are as defined below.

In a second aspect, the invention provides a composition comprising acompound according to the first aspect and a pharmaceutically acceptablecarrier.

In a third aspect, the invention provides a method of inhibiting histonedeacetylase, the method comprising contacting the histone deacetylase ora cell containing histone deacetylase, with a histone deacetylaseinhibiting amount of a compound according to the first aspect or acomposition according to second aspect.

The foregoing merely summarizes various aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below. The patent andscientific literature referred to herein establishes knowledge that isavailable to those with skill in the art. The issued patents,applications, and references that are cited herein are herebyincorporated by reference to the same extent as if each was specificallyand individually indicated to be incorporated by reference. In the caseof inconsistencies, the present disclosure will prevail.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds that are useful as inhibitorsof histone deacetylase.

In one aspect, the invention provides compound of the formula (I)

and racemic mixtures, diastereomers and enantiomers thereof andN-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein groups

Q, J, L and Z are as defined herein.

In the second aspect, the invention provides a composition comprising acompound according to the first aspect or a preferred embodiment thereofand a pharmaceutically acceptable carrier.

In the third aspect, the invention provides a method of inhibitinghistone deacetylase. In one embodiment, the method comprises contactingthe histone deacetylase with a histone deacetylase inhibiting amount ofa compound according to the first aspect or a preferred embodimentthereof. In a further embodiment of the third aspect, the methodcomprises contacting the histone deacetylase with a histone deacetylaseinhibiting amount of a composition according to the second aspect. Inyet another embodiment, the method comprises inhibiting histonedeacetylase in a cell comprising contacting the cell with a histonedeacetylase inhibiting amount of compound according to the first aspector a preferred embodiment thereof. In still another embodiment, themethod comprises inhibiting histone deacetylase in a cell comprisingcontacting the cell with a histone deacetylase inhibiting amount of acomposition according to the second aspect.

In a particularly preferred embodiment of the third aspect, compoundsaccording to the first aspect are able to cross the blood brain barrierand inhibit a histone deacetylase in a cell thereacross. In a preferredembodiment, the cell is a cell of the central nervous system, morepreferably a brain cell, more preferably a cortical cell.

In another aspect, the present invention provides a method of inhibitingHDAC in the brain of an individual. The method comprises administeringto the individual a HDAC inhibiting amount of a histone deacetylaseinhibitor according to the present invention, or a composition thereof.

In another aspect, the present invention provides a method of treating apolyglutamine (polyQ) expansion disease, comprising administering to anindividual in need of treatment a therapeutically effective amount of acompound according to the present invention, or a composition thereof.

In certain preferred embodiments, the disease is selected from the groupconsisting of Huntington's Disease (HD), Dentatorubralpallidoluysianatrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and fivespinocerebellar ataxias (SCA1, SCA2, SCA3/MJD (Machado-Joseph Disease),SCA6 and SCA7).

In a preferred embodiment, the disease is Huntington's Disease.

In preferred embodiments, the individual is a mammal, preferably aprimate, more preferably a human.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise).

The terms “treating”, “treatment”, or the like, as used herein coversthe treatment of a disease-state in an animal and includes at least oneof: (i) preventing the disease-state from occurring, in particular, whensuch animal is predisposed to the disease-state but has not yetdeveloped symptoms of having it; (ii) inhibiting the disease-state,i.e., partially or completely arresting its development; (iii) relievingthe disease-state, i.e., causing regression of symptoms of thedisease-state, or ameliorating a symptom of the disease; and (iv)reversal or regression of the disease-state, preferably eliminating orcuring of the disease. In a preferred embodiment the terms “treating”,“treatment”, or the like, covers the treatment of a disease-state in ananimal and includes at least one of (ii), (iii) and (iv) above. In apreferred embodiment of the present invention the animal is a mammal,preferably a primate, more preferably a human. As is known in the art,adjustments for systemic versus localized delivery, age, body weight,general health, sex, diet, time of administration, drug interaction andthe severity of the condition may be necessary, and will beascertainable with routine experimentation by one of ordinary skill inthe art.

As used herein, the terms “histone deacetylase” and “HDAC” are intendedto refer to any one of a family of enzymes that remove acetyl groupsfrom a protein, such as for example, the ε-amino groups of lysineresidues at the N-terminus of a histone. Unless otherwise indicated bycontext, the term “histone” is meant to refer to any histone protein,including H1, H2A, H2B, H3, H4, and H5, from any species. Preferredhistone deacetylases include class I and class II enzymes. Otherpreferred histone deacetylases include class III enzymes. Preferably thehistone deacetylase is a human HDAC, including, but not limited to,HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9,HDAC-10 and HDAC-11. In some other preferred embodiments, the histonedeacetylase is derived from a protozoal or fungal source.

The terms “histone deacetylase inhibitor” and “inhibitor of histonedeacetylase” are intended to mean a compound having a structure asdefined herein, which is capable of interacting with a histonedeacetylase and inhibiting its enzymatic activity.

The term “inhibiting histone deacetylase enzymatic activity” is intendedto mean reducing the ability of a histone deacetylase to remove anacetyl group from a protein, such as a histone. The concentration ofinhibitor which reduces the activity of a histone deacetylase to 50% ofthat of the uninhibited enzyme is determined as the IC₅₀ value. In somepreferred embodiments, such reduction of histone deacetylase activity isat least 50%, more preferably at least about 75%, and still morepreferably at least about 905. In other preferred embodiments, histonedeacetylase activity is reduced by at least 95% and more preferably byat least 99%.

Preferably, such inhibition is specific, i.e., the histone deacetylaseinhibitor reduces the ability of a histone deacetylase to remove anacetyl group from a protein, such as a histone, at a concentration thatis lower than the concentration of the inhibitor that is required toproduce another, unrelated biological effect. Preferably, theconcentration of the inhibitor required for histone deacetylaseinhibitory activity is at least 2-fold lower, more preferably at least5-fold lower, even more preferably at least 10-fold lower, and mostpreferably at least 20-fold lower than the concentration required toproduce an unrelated biological effect.

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene).All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety isA-B—.

For simplicity, reference to a “C_(n)-C_(m)” heterocyclyl or“C_(n)-C_(m)” heteroaryl means a heterocyclyl or heteroaryl having from“n” to “m” annular atoms, where “n” and “m” are integers. Thus, forexample, a C₅-C₆-heterocyclyl is a 5- or 6-membered ring having at leastone heteroatom, and includes pyrrolidinyl (C₅) and piperidinyl (C₆);C₆-heteroaryl includes, for example, pyridyl and pyrimidyl.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” is intended to mean a straight or branched chainaliphatic group having from 1 to 12 carbon atoms, preferably 1-8 carbonatoms, and more preferably 1-6 carbon atoms. Other preferred alkylgroups have from 2 to 12 carbon atoms, preferably 2-8 carbon atoms andmore preferably 2-6 carbon atoms. Preferred alkyl groups include,without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, and hexyl. A “C₀” alkyl (as in“C₀-C₃-alkyl”) is a covalent bond.

The term “alkenyl” is intended to mean an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” is intended to mean an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The terms “alkylene,” “alkenylene,” or “alkynylene” as used herein areintended to mean an alkyl, alkenyl, or alkynyl group, respectively, asdefined hereinabove, that is positioned between and serves to connecttwo other chemical groups. Preferred alkylene groups include, withoutlimitation, methylene, ethylene, propylene, and butylene. Preferredalkenylene groups include, without limitation, ethenylene, propenylene,and butenylene. Preferred alkynylene groups include, without limitation,ethynylene, propynylene, and butynylene.

The term “cycloalkyl” is intended to mean a saturated or unsaturatedmono-, bi, tri- or poly-cyclic hydrocarbon group having about 3 to 15carbons, preferably having 3 to 12 carbons, preferably 3 to 8 carbons,and more preferably 3 to 6 carbons. In certain preferred embodiments,the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclicgroup. Preferred cycloalkyl groups include, without limitation,cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone,cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

In certain preferred embodiments, the cycloalkyl group is a bridgedcycloalkyl group, preferably a C₅-C₁₀ bridged bicyclic group. In certainpreferred embodiments, the bridged cycloalkyl group is a C₅ bridgedbicyclic group. In certain preferred embodiments, the bridged cycloalkylgroup is a C₆ bridged bicyclic group. In certain preferred embodiments,the bridged cycloalkyl group is a C₇ bridged bicyclic group. In certainpreferred embodiments, the bridged cycloalkyl group is a C₈ bridgedbicyclic group. In certain preferred embodiments, the bridged cycloalkylgroup is a C₉ bridged bicyclic. In certain preferred embodiments, thebridged cycloalkyl group has a bridge of 0, 1, 2 or 3 carbon atoms. Abridge of 0 carbon atoms is a bond, and equates to a cycloalkyl groupfused to another ring structure. In certain preferred embodiments, thebridged cycloalkyl group has a bridge of 0, 1 or 3 carbon atoms. Incertain preferred embodiments, the bridged cycloalkyl group has a bridgeof 1 or 3 carbon atoms. In certain preferred embodiments, the bridgedcycloalkyl group has a bridge of 1 carbon atom. In certain preferredembodiments, the bridged cycloalkyl group has a bridge of 2 carbonatoms. In certain preferred embodiments, the bridged cycloalkyl grouphas a bridge of 3 carbon atoms. If a bridged cycloalkyl group isdescribed as “optionally substituted”, it is intended to be optionallysubstituted on any position, including the bridge. The bridgedcycloalkyl group is not limited to any particular stereochemistry.

The term “heteroalkyl” is intended to mean a saturated or unsaturated,straight or branched chain aliphatic group, wherein one or more carbonatoms in the chain are independently replaced by a heteroatom selectedfrom the group consisting of O, S(O)₀₋₂, N and N(R³³).

The term “aryl” is intended to mean a mono-, bi-, tri- or polycyclicC₆-C₁₄ aromatic moiety, preferably comprising one to three aromaticrings. Preferably, the aryl group is a C₆-C₁₀ aryl group, morepreferably a C₆ aryl group. Preferred aryl groups include, withoutlimitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

The terms “aralkyl” or “arylalkyl” is intended to mean a groupcomprising an aryl group covalently linked to an alkyl group. If anaralkyl group is described as “optionally substituted”, it is intendedthat either or both of the aryl and alkyl moieties may independently beoptionally substituted or unsubstituted. Preferably, the aralkyl groupis (C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl. For simplicity, when written as“arylalkyl” this term, and terms related thereto, is intended toindicate the order of groups in a compound as “aryl-alkyl”. Similarly,“alkyl-aryl” is intended to indicate the order of the groups in acompound as “alkyl-aryl”.

The terms “heterocyclyl”, “heterocyclic” or “heterocycle” are intendedto mean a group which is a mono-, bi-, or polycyclic structure havingfrom about 3 to about 14 atoms, wherein one or more atoms areindependently selected from the group consisting of N, O, and S. Thering structure may be saturated, unsaturated or partially unsaturated.In certain preferred embodiments, the heterocyclic group isnon-aromatic. In a bicyclic or polycyclic structure, one or more ringsmay be aromatic; for example one ring of a bicyclic heterocycle or oneor two rings of a tricyclic heterocycle may be aromatic, as in indan and9,10-dihydro anthracene. Preferred heterocyclic groups include, withoutlimitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl,piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl,and morpholino. In certain preferred embodiments, the heterocyclic groupis fused to an aryl, heteroaryl, or cycloalkyl group. Examples of suchfused heterocycles include, without limitation, tetrahydroquinoline anddihydrobenzofuran. Specifically excluded from the scope of this term arecompounds where an annular O or S atom is adjacent to another O or Satom.

In certain preferred embodiments, the heterocyclic group is a bridgedheterocyclic group, preferably a C₆-C₁₀ bridged bicyclic group, whereinone or more carbon atoms are independently replaced by a heteroatomselected from the group consisting of N, O and S. In certain preferredembodiments, the bridged heterocyclic group is a C₆ bridged bicyclicgroup. In certain preferred embodiments, the bridged heterocyclic groupis a C₇ bridged bicyclic group. In certain preferred embodiments, thebridged heterocyclic group is a C₈ bridged bicyclic group. In certainpreferred embodiments, the bridged heterocyclic group is a C₉ bridgedbicyclic. In certain preferred embodiments, the bridged heterocyclicgroup has a bridge of 0, 1, 2 or 3 carbon atoms. In certain preferredembodiments, the bridged heterocyclic group has a bridge of 0, 1 or 3carbon atoms. A bridge of 0 carbon atoms is a bond, and equates to aheterocyclic group fused to another ring structure. In certain preferredembodiments, the bridged heterocyclic group has a bridge of 1 or 3carbon atoms. In certain preferred embodiments, the bridged heterocyclicgroup has a bridge of 1 carbon atom. In certain preferred embodiments,the bridged heterocyclic group has a bridge of 2 carbon atoms. Incertain preferred embodiments, the bridged heterocyclic group has abridge of 3 carbon atoms. If a bridged heterocyclic group is describedas “optionally substituted”, it is intended to be optionally substitutedon any position, including the bridge. The bridged heterocyclic group isnot limited to any particular stereochemistry.

In certain preferred embodiments, the heterocyclic group is a heteroarylgroup. As used herein, the term “heteroaryl” is intended to mean amono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms,preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electronsshared in a cyclic array; and having, in addition to carbon atoms,between one or more heteroatoms independently selected from the groupconsisting of N, O, and S. For example, a heteroaryl group may bepyrimidinyl, pyridinyl, benzimidazolyl, thienyl, benzothiazolyl,benzofuranyl and indolinyl. Preferred heteroaryl groups include, withoutlimitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl,thiazolyl, and isoxazolyl.

The terms “arylene,” “heteroarylene,” or “heterocyclylene” are intendedto mean an aryl, heteroaryl, or heterocyclyl group, respectively, asdefined hereinabove, that is positioned between and serves to connecttwo other chemical groups.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl), thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, triazolyl(e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl), and xanthenyl.

Aromatic polycycles include, but are not limited to, bicyclic andtricyclic fused ring systems, including for example naphthyl.

Non-aromatic polycycles include, but are not limited to, bicyclic andtricyclic fused ring systems where each ring can be 4-9 membered andeach ring can containing zero, 1 or more double and/or triple bonds.Suitable examples of non-aromatic polycycles include, but are notlimited to, decalin, octahydroindene, perhydrobenzocycloheptene andperhydrobenzo-[f]-azulene.

Polyheteroaryl groups include bicyclic and tricyclic fused rings systemswhere each ring can independently be 5 or 6 membered and contain one ormore heteroatom, for example, 1, 2, 3 or 4 heteroatoms, independentlychosen from O, N and S such that the fused ring system is aromatic.Suitable examples of polyheteroaryl ring systems include quinoline,isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole,benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline,and the like.

Non-aromatic polyheterocyclic groups include but are not limited tobicyclic and tricyclic ring systems where each ring can be 4-9 membered,contain one or more heteratom, for example 1, 2, 3 or 4 heteratoms,independently chosen from O, N and S, and contain zero, or one or moreC—C double or triple bonds. Suitable examples of non-aromaticpolyheterocycles include but are not limited to, hexitol,cis-perhydro-cyclohepta[b]pyridinyl, decahydro-benzo[f][1,4]oxazepinyl,2,8-dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2-b]thiophene,perhydropyrrolo[3,2-b]pyrrole, perhydronaphthyridine,perhydrop-1H-dicyclopenta[b,e]pyran.

Mixed aryl and non-aryl polyheterocycle groups include but are notlimited to bicyclic and tricyclic fused ring systems where each ring canbe 4-9 membered, contain one or more heteroatom independently chosenfrom O, N and S and at least one of the rings must be aromatic. Suitableexamples of mixed aryl and non-aryl polyheteorcycles include2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline,5,11-dihydro-10H-dibenz[b,e][1,4]diazepine,5H-dibenzo[b,e][1,4]diazepine,1,2-dihydropyrrolo[3,4-b][1,5]benzodiazepine,1,5-dihydropyrido[2,3-b][1,4]diazepin-4-one,1,2,3,4,6,11-hexhydro-benzo[b]pyrido[2,3-e][1,4]diazepine-5-one,methylenedioxyphenyl, bis-methylenedioxyphenyl,1,2,3,4-tetrahydronaphthalene, dibenzosuberane dihydroanthracene and9H-fluorene.

As employed herein, and unless stated otherwise, when a moiety (e.g.,alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, etc.) isdescribed as “optionally substituted” it is meant that the groupoptionally has from one to four, preferably from one to three, morepreferably one or two, non-hydrogen substituents. Suitable substituentsinclude, without limitation, halo, hydroxy, oxo (e.g., an annular —CH—substituted with oxo is —C(O)—) nitro, halohydrocarbyl, hydrocarbyl,alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy,aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl,acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl,alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl,acyloxy, cyano, and ureido groups. Preferred substituents, which arethemselves not further substituted (unless expressly stated otherwise)are:

-   -   (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,        guanidino,    -   (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈        alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈ acylamino,        C₁-C₈ alkylthio, arylalkylthio, arylthio, C₁-C₈ alkylsulfinyl,        arylalkylsulfinyl, arylsulfinyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅        N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy,        arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle        or another aryl ring, C₃-C₇ heterocycle, C₅-C₁₅ heteroaryl or        any of these rings fused or spiro-fused to a cycloalkyl,        heterocyclyl, or aryl, wherein each of the foregoing is further        optionally substituted with one more moieties listed in (a),        above; and    -   (c) —(CR³²R^(33a))_(s)—NR³⁰R³¹, wherein s is from 0 (in which        case the nitrogen is directly bonded to the moiety that is        substituted) to 6, R³² and R^(33a) are each independently        hydrogen, halo, hydroxyl or C₁-C₄alkyl, and R³⁰ and R³¹ are each        independently hydrogen, cyano, oxo, hydroxyl, —C₁-C₈ alkyl,        C₁-C₈ heteroalkyl, C₁-C₈ alkenyl, carboxamido, C₁-C₃        alkyl-carboxamido, carboxamido-C₁-C₃ alkyl, amidino,        C₂-C₈hydroxyalkyl, C₁-C₃ alkylaryl, aryl-C₁-C₃ alkyl, C₁-C₃        alkylheteroaryl, heteroaryl-C₁-C₃ alkyl, C₁-C₃        alkylheterocyclyl, heterocyclyl-C₁-C₃ alkyl C₁-C₃        alkylcycloalkyl, cycloalkyl-C₁-C₃ alkyl, C₂-C₈ alkoxy, C₂-C₈        alkoxy-C₁-C₄alkyl, C₁-C₈ alkoxycarbonyl, aryloxycarbonyl,        aryl-C₁-C₃ alkoxycarbonyl, heteroaryloxycarbonyl,        heteroaryl-C₁-C₃ alkoxycarbonyl, C₁-C₈ acyl, C₀-C₈        alkyl-carbonyl, aryl-C₀-C₈ alkyl-carbonyl, heteroaryl-C₀-C₈        alkyl-carbonyl, cycloalkyl-C₀-C₈ alkyl-carbonyl, C₀-C₈        alkyl-NH-carbonyl, aryl-C₀-C₈ alkyl-NH-carbonyl,        heteroaryl-C₀-C₈ alkyl-NH-carbonyl, cycloalkyl-C₀-C₈        alkyl-NH-carbonyl, C₀-C₈ alkyl-O-carbonyl, aryl-C₀-C₈        alkyl-O-carbonyl, heteroaryl-C₀-C₈ alkyl-O-carbonyl,        cycloalkyl-C₀-C₈ alkyl-O-carbonyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, heteroarylalkylsulfonyl,        heteroarylsulfonyl, C₁-C₈ alkyl-NH-sulfonyl,        arylalkyl-NH-sulfonyl, aryl-NH-sulfonyl,        heteroarylalkyl-NH-sulfonyl, heteroaryl-NH-sulfonyl aroyl, aryl,        cycloalkyl, heterocyclyl, heteroaryl, aryl-C₁-C₃ alkyl-,        cycloalkyl-C₁-C₃ alkyl-, heterocyclyl-C₁-C₃ alkyl-,        heteroaryl-C₁-C₃ alkyl-, or protecting group, wherein each of        the foregoing is further optionally substituted with one more        moieties listed in (a), above; or R³⁰ and R³¹ taken together        with the N to which they are attached form a heterocyclyl or        heteroaryl, each of which is optionally substituted with from 1        to 3 substituents selected from the group consisting of (a)        above, a protecting group, and (X³⁰—Y³¹—), wherein said        heterocyclyl may also be bridged (forming a bicyclic moiety with        a methylene, ethylene or propylene bridge); wherein X³⁰ is        selected from the group consisting of C₁-C₈alkyl, C₂-C₈alkenyl-,        C₂-C₈alkynyl-, —C₀-C₃alkyl —C₂-C₈alkenyl-C₀-C₃alkyl,        C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl, C₀-C₃alkyl-O—C₀-C₃alkyl-,        HO—C₀-C₃alkyl-, C₀-C₄alkyl-N(R³⁰)—C₀-C₃alkyl-,        N(R³⁰)(R³¹)—C₀-C₃alkyl-, N(R³⁰)(R³¹)—C₀-C₃alkenyl-,        N(R³⁰)(R³¹)—C₀-C₃alkynyl-, (N(R³⁰)(R³¹))₂—C═N—,        C₀-C₃alkyl-S(O)₀₋₂—C₀-C₃alkyl-, CF₃—C₀-C₃alkyl-,        C₁-C₈heteroalkyl, aryl, cycloalkyl, heterocyclyl, heteroaryl,        aryl-C₁-C₃alkyl-, cycloalkyl-C₁-C₃alkyl-,        heterocyclyl-C₁-C₃alkyl-, heteroaryl-C₁-C₃alkyl-,        N(R³⁰)(R³¹)-heterocyclyl-C₁-C₃alkyl-, wherein the aryl,        cycloalkyl, heteroaryl and heterocycyl are optionally        substituted with from 1 to 3 substituents from (a); and Y³¹ is        selected from the group consisting of a direct bond, —O—,        —N(R³⁰)—, —C(O)—, —O—C(O)—, —C(O)—O—, —N(R³⁰)—C(O)—,        —C(O)—N(R³⁰)—, —N(R³⁰)—C(S)—, —C(S)—N(R³⁰)—,        —N(R³⁰)—C(O)—N(R³¹)—, —N(R³⁰)—C(NR³⁰)—N(R³¹)—, —N(R³⁰)—C(NR³¹)—,        —C(NR³¹)—N(R³⁰), —N(R³⁰)—C(S)—N(R³¹)—, —N(R³⁰)—C(O)—O—,        —O—C(O)—N(R³¹)—, —N(R³⁰)—C(S)—O—, —O—C(S)—N(R³¹)—, —S(O)₀₋₂—,        —SO₂N(R³¹)—, —N(R³¹)—SO₂— and —N(R³⁰)—SO₂N(R³¹)—.

As a non-limiting example, substituted phenyls include 2-fluorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl.As another non-limiting example, substituted n-octyls include2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within thisdefinition are methylenes (—CH₂—) substituted with oxygen to formcarbonyl —CO—.

When there are two optional substituents bonded to adjacent atoms of aring structure, such as for example phenyl, thiophenyl, or pyridinyl,the substituents, together with the atoms to which they are bonded,optionally form a 5- or 6-membered cycloalkyl or heterocycle having 1,2, or 3 annular heteroatoms.

In a preferred embodiment, hydrocarbyl, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromaticpolycycle, non-aromatic polycycle, polyheteroaryl, non-aromaticpolyheterocyclic and mixed aryl and non-aryl polyheterocycle groups areunsubstituted.

In other preferred embodiments, hydrocarbyl, alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aromaticpolycycle, non-aromatic polycycle, polyheteroaryl, non-aromaticpolyheterocyclic and mixed aryl and non-aryl polyheterocycle groups aresubstituted with from 1 to 3 independently selected substituents.

Preferred substituents on alkyl groups include, but are not limited to,hydroxyl, halogen (e.g., a single halogen substituent or multiple halosubstituents; in the latter case, groups such as CF₃ or an alkyl groupbearing more than one Cl), cyano, nitro, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, heterocycle, aryl, —OR^(u), —SR^(u), —S(═O)R^(y),—S(═O)₂R^(y), —P(═O)₂R^(y), —S(═O)₂OR^(y), —P(═O)₂OR^(y), —NR^(v)R^(w),—NR^(v)S(═O)₂R^(y), —NR^(v)P(═O)₂R^(y), —S(═O)₂NR^(v)R^(w),—P(═O)₂NR^(v)R^(w), —C(═O)OR^(y), —C(═O)R^(w), —C(═O)NR^(v)R^(w),—OC(═O)R^(w), —OC(═O)NR^(v)R^(w), —NR^(v)C(═O)OR^(y),—NR^(x)C(═O)NR^(v)R^(w), —NR^(x)S(═O)₂NR^(v)R^(w),—NR^(x)P(═O)₂NR^(v)R^(w), —NR^(v)C(═O)R^(k) or —NR^(v)P(═O)₂R^(y),wherein R^(k) is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle or aryl; R^(v), R^(w) and R^(x) are independentlyhydrogen, alkyl, cycloalkyl, heterocycle or aryl, or said R^(w) andR^(w) together with the N to which they are bonded optionally form aheterocycle; and R^(y) is alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, heterocycle or aryl. In the aforementioned exemplarysubstituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl,cycloalkenyl, heterocycle and aryl can themselves be optionallysubstituted.

Preferred substituents on alkenyl and alkynyl groups include, but arenot limited to, alkyl or substituted alkyl, as well as those groupsrecited as preferred alkyl substituents.

Preferred substituents on cycloalkyl groups include, but are not limitedto, nitro, cyano, alkyl or substituted alkyl, as well as those groupsrecited about as preferred alkyl substituents. Other preferredsubstituents include, but are not limited to, spiro-attached or fusedcyclic substituents, preferably spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted.

Preferred substituents on cycloalkenyl groups include, but are notlimited to, nitro, cyano, alkyl or substituted alkyl, as well as thosegroups recited as preferred alkyl substituents. Other preferredsubstituents include, but are not limited to, spiro-attached or fusedcyclic substituents, especially spiro-attached cycloalkyl,spiro-attached cycloalkenyl, spiro-attached heterocycle (excludingheteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cycloalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted.

Preferred substituents on aryl groups include, but are not limited to,nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substitutedcycloalkenyl, cyano, alkyl or substituted alkyl, as well as those groupsrecited above as preferred alkyl substituents. Other preferredsubstituents include, but are not limited to, fused cyclic groups,especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, orfused aryl, where the aforementioned cycloalkyl, cylcoalkenyl,heterocycle and aryl substituents can themselves be optionallysubstituted. Still other preferred substituents on aryl groups (phenyl,as a non-limiting example) include, but are not limited to, haloalkyland those groups recited as preferred alkyl substituents.

Preferred substituents on heterocylic groups include, but are notlimited to, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, nitro, oxo (i.e., ═O), cyano, alkyl,substituted alkyl, as well as those groups recited as preferred alkylsubstituents. Other preferred substituents on heterocyclic groupsinclude, but are not limited to, spiro-attached or fused cylicsubstituents at any available point or points of attachement, morepreferably spiro-attached cycloalkyl, spiro-attached cycloalkenyl,spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl,fused cycloakenyl, fused heterocycle and fused aryl, where theaforementioned cycloalkyl, cycloalkenyl, heterocycle and arylsubstituents can themselves be optionally substituted.

In a preferred embodiment, a heterocyclic group is substituted oncarbon, nitrogen and/or sulfur at one or more positions. Preferredsubstituents on nitrogen include, but are not limited to N-oxide, alkyl,aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl,alkoxycarbonyl, or aralkoxycarbonyl. Preferred substituents on sulfurinclude, but are not limited to, oxo and C₁₋₆alkyl. In certain preferredembodiments, nitrogen and sulfur heteroatoms may independently beoptionally oxidized and nitrogen heteroatoms may independently beoptionally quaternized.

Especially preferred substituents on alkyl groups include halogen andhydroxy.

Especially preferred substituents on ring groups, such as aryl,heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy andalkyl.

Preferred substituents on aromatic polycycles include, but are notlimited to, oxo, C₁-C₆alkyl, cycloalkylalkyl (e.g. cyclopropylmethyl),oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketones,nitrile, carboxyalkyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl andOR^(aa), such as alkoxy, wherein R^(aa) is selected from the groupconsisting of H, C₁-C₆alkyl, C₄-C₉cycloalkyl, C₄-C₉heterocycloalkyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH₂)₀₋₆Z^(a)R^(bb),wherein Z^(a) is selected from the group consisting of O, NR^(cc), S andS(O), and R^(bb) is selected from the group consisting of H, C₁-C₆alkyl,C₄-C₉cycloalkyl, C₄-C₉heterocycloalkyl, C₄-C₉heterocycloalkylalkyl,aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, (e.g.benzyl), and heteroarylalkyl (e.g. pyridylmethyl); and R^(cc) isselected from the group consisting of H, C₁-C₆alkyl, C₄-C₉cycloalkyl,C₄-C₉heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g. benzyl),heteroarylalkyl (e.g. pyridylmethyl) and amino acyl.

Preferred substituents on non-aromatic polycycles include, but are notlimited to, oxo, C₃-C₉cycloalkyl, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. Unless otherwise noted,non-aromatic polycycle substituents include both unsubstitutedcycloalkyl groups and cycloalkyl groups that are substituted by one ormore suitable substituents, including but not limited to, C₁-C₆alkyl,oxo, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR^(aa), suchas alkoxy. Preferred substituents for such cycloalkyl groups includehalo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

Preferred substituents on carbon atoms of polyheteroaryl groups includebut are not limited to, straight and branched optionally substitutedC₁-C₆alkyl, unsaturation (i.e., there are one or more double or tripleC—C bonds), acyl, oxo, cycloalkyl, halo, oxyalkyl, alkylamino,aminoalkyl, acylamino, OR^(aa) (for example alkoxy), and a substituentof the formula —O—(CH₂CH═CH(CH₃)(CH₂))₁₋₃H. Examples of suitablestraight and branched C₁-C₆alkyl substituents include but are notlimited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl,t-butyl and the like. Preferred substituents include halo, hydroxy,alkoxy, oxyalkyl, alkylamino and aminoalkyl. Preferably substitutions onnitrogen atoms include, for example by N-oxide or R^(cc). Preferredsubstituents on nitrogen atoms include H, C₁-C₄alkyl, acyl, aminoacyland sulfonyl. Preferably sulfur atoms are unsubstituted. Preferredsubstituents on sulfur atoms include but are not limited to oxo andlower alkyl.

Preferred substituents on carbon atoms of non-aromatic polyheterocyclicgroups include but are not limited to straight and branched optionallysubstituted C₁-C₆alkyl, unsaturation (i.e., there are one or more doubleor triple C—C bonds), acyl, oxo, cycloalkyl, halo, oxyalkyl, alkylamino,aminoalkyl, acylamino and OR^(aa), for example alkoxy. Examples ofsuitable straight and branched C₁-C₆alkyl substituents include but arenot limited to methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl,t-butyl and the like. Preferred substituents include halo, hydroxy,alkoxy, oxyalkyl, alkylamino and aminoalkyl. Preferably substitutions onnitrogen atoms include, for example, N-oxide or R^(cc). Preferred Nsubstituents include H, C₁-C₄ alkyl, acyl, aminoacyl and sulfonyl.Preferably, sulfur atoms are unsubstituted. Preferred S substituentsinclude oxo and lower alkyl.

Preferred substituents on mixed aryl and non-aryl polyheterocycle groupsinclude, but are not limited to, nitro or as described above fornon-aromatic polycycle groups. Preferred substituents on carbon atomsinclude, but are not limited to, —N—OH, ═N—OH, optionally substitutedalkyl, unsaturation (i.e., there are one or more double or triple C—Cbonds), oxo, acyl, cycloalkyl, halo, oxyalkyl, alkylamino, aminoalkyl,acylamino and OR^(aa), for example alkoxy. Preferably substitutions onnitrogen atoms include, for example, N-oxide or R^(cc). Preferred Nsubstituents include H, C₁₋₄alkyl, acyl aminoacyl and sulfonyl.Preferably sulfur atoms are unsubstituted. Preferred S substituentsinclude oxo and lower alkyl.

A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to allhydrogens have been replaced with one or more halo.

The term “halogen” or “halo” is intended to mean chlorine, bromine,fluorine, or iodine. As herein employed, the term “acyl” refers to analkylcarbonyl or arylcarbonyl substituent. The term “acylamino” refersto an amide group attached at the nitrogen atom (i.e., R—CO—NH—). Theterm “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally optionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” is intended to mean a chemical moiety comprising oneor more unpaired electrons.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 9-14membered bi-cyclic moieties fused to the parent cyclic moiety to form abi- or tri-cyclic fused ring system. Substituents on cyclic moietiesalso include 5-6 membered mono- and 9-14 membered bi-cyclic moietiesattached to the parent cyclic moiety by a covalent bond to form a bi- ortri-cyclic bi-ring system. For example, an optionally substituted phenylincludes, but is not limited to, the following:

An “unsubstituted” moiety (e.g., unsubstituted cycloalkyl, unsubstitutedheteroaryl, etc.) means that moiety as defined above that does not havean optional substituent. Thus, for example, “unsubstituted aryl” doesnot include phenyl substituted with a halo.

The term “protecting group” is intended to mean a group used insynthesis to temporarily mask the characteristic chemistry of afunctional group because it interferes with another reaction. A goodprotecting group should be easy to put on, easy to remove and in highyielding reactions, and inert to the conditions of the reactionrequired. A protecting group or protective group is introduced into amolecule by chemical modification of a functional group in order toobtain chemoselectivity in a subsequent chemical reaction. One skilledin the art will recognize that during any of the processes forpreparation of the compounds in the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as but not limited to Bn- (or—CH₂Ph), —CHPh₂, alloc (or CH₂═CH—CH₂—O—C(O)—), BOC—, -Cbz (or Z-),—F-moc, —C(O)—CF₃, N-Phthalimide, 1-Adoc-, TBDMS-, TBDPS-, TMS-, TIPS-,IPDMS-, —SiR₃, SEM-, t-Bu-, Tr-, THP- and Allyl-. These protectinggroups may be removed at a convenient stage using methods known from theart.

The term “therapeutically effective amount” as that term is used hereinrefers to an amount which elicits the desired therapeutic effect. Thetherapeutic effect is dependent upon the disease being treated and theresults desired. As such, the therapeutic effect can be a decrease inthe severity of symptoms associated with the disease and/or inhibition(partial or complete) of progression of the disease. Further, thetherapeutic effect can be inhibition of HDAC in the brain. The amountneeded to elicit the therapeutic response can be determined based on theage, health, size and sex of the patient. Optimal amounts can also bedetermined based on monitoring of the patient's response to treatment.Administration may be by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain particularly preferredembodiments, compounds of the invention are administered intravenouslyin a hospital setting. In certain other preferred embodiments,administration may preferably be by the oral route.

Some compounds of the invention may have one or more chiral centersand/or geometric isomeric centers (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers. The invention also comprises alltautomeric forms of the compounds disclosed herein.

The present invention also includes prodrugs of compounds of theinvention. The term “prodrug” is intended to represent covalently bondedcarriers, which are capable of releasing the active ingredient when theprodrug is administered to a mammalian subject. Release of the activeingredient occurs in vivo. Prodrugs can be prepared by techniques knownto one skilled in the art. These techniques generally modify appropriatefunctional groups in a given compound. These modified functional groupshowever regenerate original functional groups by routine manipulation orin vivo. Prodrugs of compounds of the invention include compoundswherein a hydroxy, amino, carboxylic, or a similar group is modified.Examples of prodrugs include, but are not limited to esters (e.g.,acetate, formate, and benzoate derivatives), carbamates (e.g.,N,N-dimethylaminocarbonyl) of hydroxy or amino functional groups incompounds of Formula (I)), amides (e.g., trifluoroacetylamino,acetylamino, and the like), and the like.

The compounds of the invention may be administered as is or as aprodrug, for example in the form of an in vivo hydrolyzable ester or invivo hydrolyzable amide. An in vivo hydrolyzable ester of a compound ofthe invention containing carboxy or hydroxy group is, for example, apharmaceutically acceptable ester which is hydrolyzed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include C₁₋₆-alkoxymethylesters (e.g., methoxymethyl), C₁₋₆-alkanoyloxymethyl esters (e.g., forexample pivaloyloxymethyl), phthalidyl esters,C₃₋₈-cycloalkoxycarbonyloxyC₁₋₆-alkyl esters (e.g.,1-cyclohexylcarbonyloxyethyl); 1,3-dioxolen-2-onylmethyl esters (e.g.,5-methyl-1,3-dioxolen-2-onylmethyl; and C₁₋₆-alkoxycarbonyloxyethylesters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at anyappropriate carboxy group in the compounds of this invention.

An in vivo hydrolyzable ester of a compound of the invention containinga hydroxy group includes inorganic esters such as phosphate esters andα-acyloxyalkyl ethers and related compounds which as a result of the invivo hydrolysis of the ester breakdown to give the parent hydroxy group.Examples of α-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolyzableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN—(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),N,N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.A suitable value for an in vivo hydrolyzable amide of a compound of theinvention containing a carboxy group is, for example, a N—C₁₋₆-alkyl orN,N-di-C₁₋₆-alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

For simplicity, and unless stated otherwise, a moiety is written in thedirection corresponding to the order given in Formula (I). For example,if moiety J is —C₀₋₆alkyl-aryl-C₂₋₆heteroalkyl-, it is meant that the—C₀₋₆alkyl-portion is attached to Q and the —C₂₋₆heteroalkyl-portion isattached to L.

The foregoing merely summarizes some aspects and preferred embodimentsthereof and is not intended to be limiting in nature. These aspects andpreferred embodiments thereof are described more fully below.

Compounds

In a first aspect, the invention provides novel inhibitors of histonedeacetylase. In a first embodiment, the novel inhibitors of histonedeacetylase are represented by Formula (I):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, and racemic mixtures, diastereomers andenantiomers thereof, whereinZ is selected from the group consisting of —N(R¹)OR² and H;L is selected from the group consisting of a covalent bond and —N(OR²)—;wherein, when L is —N(OR²)—, Z is H; andwherein, when Z is H, L is —N(OR²)—;J is selected from the group consisting of a covalent bond, ═CH—,—C₁-C₈alkyl-, —C₀-C₃alkyl-C₁-C₈heteroalkyl-C₀-C₃alkyl-,—C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃alkyl-,—C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl-, —C₀-C₆alkyl-aryl-C₀-C₆alkyl-,—C₀-C₆alkyl-aryl-C₂-C₆heteroalkyl-,—C₀-C₃alkyl-C₁-C₆heteroalkyl-aryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₁-C₆heteroalkyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkyl-cycloalkyl-C₀-C₆alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-,—C₄-C₆heterocyclyl-aryl-C₀-C₆alkyl-,—C₄-C₆heterocyclyl-aryl-C₀-C₆heteroalkyl-,—C₀-C₆alkyl-C₄-C₆heterocyclyl-C₀-C₆alkyl-,—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkylheteroaryl-C₀-C₆heteroalkyl-,—C₄-C₆heterocyclyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkynyl-, —C₀-C₆alkyl-heteroaryl-C₂-C₆alkynyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkynyl-C₂-C₆alkenyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-heteroaryl-C₂-C₆alkenyl-,—C₀-C₃alkyl-C₂-C₆alkenyl-aryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkenyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkynyl-aryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkynyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkylaryl-aryl-C₀-C₆alkyl-,—C₀-C₆alkylaryl-heteroaryl-C₀-C₆alkyl-,—C₀-C₃alkyl-heteroaryl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heteroaryl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-aryl-C₀-C₃alkyl-, and—C₀-C₆alkyl-C₃-C₆cycloalkyl-C₀-C₆alkyl-, wherein each alkyl, alkenyl,alkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkylmoiety is optionally substituted, and wherein when J is ═CH—, Q is acovalent bond and B is attached through a carbon sp² to J;Q is selected from the group consisting of an optionally substituted:

or where possible, an (R,R) or (S,S) enantiomer or a mixture ofenantiomers thereof,wherein G and G¹ are independently selected from carbon and N; thevariables l, m, n, o and p denote numbers that are each independentlyselected from 0, 1, 2 or 3 provided that the sum total of l, m, n, o andp is 4, 5, 6 or 7, such that the group represented by Q comprises a 6,7, 8 or 9 membered bridged or fused heterocyclyl, respectively, andfurther provided that when G and G¹ are both N then the sum total of land o is not zero, and the sum total of m and p is not zero, and whereinn is an integer ranging from 0 to 3; (preferably, Q comprises a 7 or8-membered ring; in one particular embodiment, n is zero, such that Qcomprises a fused bicyclic ring);U is selected from the group consisting of —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-,—C₁-C₈alkyl-, —C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,—C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond and—O—C₂-C₄alkyl-; andU¹ is selected from the group consisting of H, —C(R¹)(R²)—,—C₀-C₈alkyl-C(O)—C₀-C₃alkyl-, —C₁-C₈alkyl-,—C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-, —C(R¹)(R²)—N(R³)—C(O)—C₀-C₃alkyl-,—C(R¹)(R²)—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-,—C(R¹)(R²)—O—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,—C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond,(R³)(R^(3a))N—C₂-C₄alkyl-, —O—C₂-C₄alkyl-, and R³—O—C₂-C₄alkyl-;orQ is selected from the group consisting of a covalent bond,—C₁-C₈alkyl-, —C₁-C₈alkyl-, —C₁-C₈heterocyclyl-, ═N—O—,—C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-O—C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)₀₋₂—C₀-C₃alkyl-, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-C(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-O—C₀-C₃alkyl-,—C₀-C₆alkyl-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)₀₋₂—N(R³)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—N(R³)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-O—C(O)—O-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—O-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-, —C₀-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₄alkyl-,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C₀-C₆alkyl-SO₂—N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—SO₂—C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-S-C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl-, ═N—O—C₀-C₃alkyl-,-heterocyclyl-C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C(O)—C₀-C₆alkyl-bridgedheterocyclyl-C₀-C₃alkyl-,—N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-SO₂—N(R³)—, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl moiety is optionally substituted; wherein

is selected from the group consisting of b-1a to b-1k and b-1 to b-125,and wherein when Q is attached to

or ═N—O—C₀₋₃alkyl, it is attached through carbon Sola-Penna et al.² in

and wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl andalkenyl moiety is optionally substituted; and wherein when Q is acovalent bond and J is attached to

then it is attached through carbon sp² in

orwhen

is selected from the group consisting of b-1 to b-121 and is attached toQ via a N in

then Q is selected from the group consisting of a covalent bond,—C(O)—C₁-C₃alkyl-O—, —C₁-C₈alkyl-, —C₂-C₆alkyl-N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C₀-C₆alkyl-C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-O—C₀-C₃alkyl-, —C₁-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-,—C₁-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-, —C₂-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl,—C₂-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₃alkyl,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C(O)—O—C₀-C₄alkyl,—C₀-C₆alkyl-S(O)₂—N(R³)—C₀-C₃alkyl, —C₂-C₆alkyl-N(R³)—S(O)₂—C₀-C₃alkyl,—C₂-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₂-C₆alkyl-S—C₀-C₃alkyl,—C₂-C₆alkyl-S(O)—C₀-C₃alkyl, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl,—C₂-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl, —C₂-C₃alkyl-C═N—O—C₀-C₃alkyl,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-S(O₂)—N(R³)—,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,heterocyclyl and alkenyl moiety is optionally substituted, and whereinthe heterocyclyl moiety is optionally bridged with —(CH₂)₀₋₃—;R¹ and R² are independently selected from the group consisting of —H,C₁-C₆alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and a protectinggroup;each R³ is independently selected from the group consisting of —H,alkyl, C₀-C₃alkyl-heterocyclyl, C₁-C₃alkyl-C₂-C₆alkenyl,C₁-C₃alkyl-C₂-C₃alkynyl, —C₂-C₄alkyl-OR¹, —C₂-C₄alkyl-N ° C.,—C₂-C₄alkyl-NR¹R², heteroalkyl, C₀-C₆alkylheteroaryl, C(O)CF₃,—C(O)—NH₂, —C(O)—NR^(3b)R^(3c), —C(O)—NR¹R², —C(O)—OR¹, —S(O)₂—NR¹R²,—S(O)₂—R¹, —C(O)—R¹, —C₃-C₆cycloalkyl, —C₀-C₃alkyl-C₃-C₇cycloalkyl,—C₁-C₆alkylaryl, aryl, C₀-C₃alkyl-heteroaryl and heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl,aryl and heteroaryl moiety is optionally substituted with from one tothree independently selected substituents;each R^(3a) is independently selected from the group consisting of —H,alkyl, heterocyclyl, C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹,heteroalkyl, heteroaryl, C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂,—C₃-C₆cycloalkyl, -alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl,alkylheteroaryl and heteroaryl, covalent bond, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl moiety is optionally substituted;wherein R³ and R^(3a), together with the atom to which they areattached, optionally form a heterocyclic ring, wherein the heterocyclylmoiety is optionally substituted;wherein R^(3a) and R^(3c), together with the atom to which they areattached, optionally form a heterocyclic ring, wherein the heterocyclylmoiety is optionally substituted;provided that

is absent when Q is structure (a-1), (a-2), (a-3), (a-20) or when U¹ isH, N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-;

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, heterocyclyl, cycloalkyl,heterocyclyl-alkyl, cycloalkyl-alkyl, C₁-C₁₀alkyl,(aryl)₂-CH—C₀-C₆alkyl-, (aryl)(heteroaryl)CH—C₀-C₆alkyl- and(heteroaryl)₂CH—C₀-C₆alkyl-, each of which is optionally substituted; or

is a radical selected from the group consisting of

wherein

are independently selected from phenyl, a 5- or 6-membered heteroaryland heterocyclyl, each of which is optionally substituted with one tothree independently selected substituents;provided that when

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, heterocyclyl, cycloalkyl,heterocyclyl-alkyl, cycloalkyl-alkyl, C₁-C₁₀alkyl,(aryl)₂-CH—C₀-C₆alkyl-, (aryl)(heteroaryl)CH—C₀-C₆alkyl- and(heteroaryl)₂CH—C₀-C₆alkyl-, each of which is optionally substituted,then Q is selected from the group consisting of a-3, a-4, a-5, a-6, a-7,a-8, a-9, a-10, a-11, a-12, a-13 and a-14,whereineach A is independently selected from the group consisting of N,—N-oxide, —CH═ and —C(R⁴)═, wherein no more than two A per 5 or 6membered ring are N in a

group, and wherein no more than one A is —N-oxide;the group M¹-M² is selected from the group consisting of a covalentbond, —N(R³)CH₂—, —CH₂N(R³)—, —S(O)₀₋₂—CH₂—, —CH₂S(O)₀₋₂—, —O—CH₂—,—CH₂—O—, —C(O)N(R³)—, —C(O)—O—, —C(O)—CH₂—, —CH(OH)—CH₂—, —CH(F)—CH₂—,—CH₂—C(O)—, —CH₂—CH(OH)—, —CH₂—CH(F)—, —N(R³)—C(O)—, —SO₂N(R³)—,—N(R³)SO₂—, —CH(R⁴)CH₂—, —CH₂CH(R⁴)—, —N═C(R⁴)—, —C(R⁴)═N—, —CH₂—CH₂—,—CH═CH—, —CH(R³)—CH(R³)—, —C(R³)═C(R³)—, —C(R⁴)═C(R⁴)—, —CF═CH—,—CH═CF—,

—CH₂—, —C(R³)(R^(3a))—, —S(O)₀₋₂—, —N(R³)—, or absent;M³ is selected from the group consisting of

or M³ is

wherein Q is attached to

or ═N—O—C₀₋₃alkyl, or J is attached to

via ═CH—,

wherein * represents the point of attachment to Q;M⁴ is selected from the group consisting of

and covalent bond;wherein, when M¹-M² is a covalent bond, M⁴ is selected from the groupconsisting of

the groups D¹-D² and D^(1a)-D^(2a) are selected from the groupconsisting of

wherein, * represents the point of attachment to Q;D³ is selected from the group consisting of a covalent bond,

wherein the

are optionally substituted;D⁴ is selected from the group consisting of

wherein the

is optionally substituted;the group E¹-E² is selected from the group consisting of

wherein * represents the point of attachment to Q; andE³ is selected from the group consisting of —C(O)—, —C(S)—, —CH₂—,—C(OH)₂— and —C═N(R³)—;andR⁴ is independently selected from the group consisting of —H,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkyl-R³, —C₀-C₆alkyl-OR³,—C₀-C₆alkyl-OR¹, —C₀-C₆alkyl-C(O)—OR³, —C₀-C₆alkyl-C(O)NR³R^(3a),—CH═CH—C(O)—OR³, —CH═CH—C(O)—N(R³)(R^(3a)), —N(R³)—C(O)—CF³,—N(R³)—C₂-C₆alkyl-N(R³)(R^(3a)), —C₀-C₆alkyl-N(R³)(R^(3a)),—N(R³)—C(O)—C₁-C₆alkyl-R³, —N(R³)—S(O)₂—C₁-C₆alkyl-R³,—S(O)₂—N(R³)R^(3a), —O—C₂-C₆alkyl-N(R³)(R^(3a)), —O—C₂-C₆alkyl-OR¹,—S—R³, —S(O)—C₁-C₆alkyl-R³, —S(O)₂—C₁-C₆alkyl-R³, C₃-C₆cycloalkyl,heterocyclyl, C₄-C₇heterocyclyl-R³, —O—C₂-C₄alkyl-heterocyclyl,—O-heterocyclyl-C(O)—OR³, —O—C₀-C₄alkyl-aryl, —O—C₀-C₄alkyl-heteroaryl,—O—C(O)—NR³—C₀-C₄alkyl-aryl, —O—C(O)—NR³—C₀-C₄alkyl-heteroaryl,—O—C₀-C₄alkyl-heterocyclylaryl, —O—C₀-C₄alkyl-heterocyclyl-heteroaryl,—N(R³)—C₂-C₄alkyl-heterocyclyl,—N(R³)C(O)N(R³)—C₀-C₄alkyl-heterocyclyl-R³, —C₀-C₄alkyl-OC(O)—R³,—C₀-C₄alkyl-N(R³)C(O)—O—R³, —C₀-C₄alkyl-heterocyclyl-C(O)—O—R³,—N(R³)—C₂-C₄alkyl-heterocyclyl, F, Cl, Br, I, NO₂, —CF₃, —OCF₃, —OCHF₂,—SCF₃, —SF₅, —SO₃H, —CN, —C₁-C₆ alkylaryl, aryl, heteroaryl, cycloalkyl,—C₁-C₆ alkylheteroaryl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl and heteroaryl moeity of theaforementioned R⁴ is optionally substituted;or

is selected from the group consisting of structures b-1a to b-1k and(b-1) to (b-125) and Q-J-L taken together is selected from the groupconsisting of —C₃-C₈alkyl-, —C(O)—C₃-C₈alkyl-,—C₀-C₃alkyl-O—C₃-C₈alkyl-, —C₀-C₃alkyl-C₁-C₄alkenyl-C₀-C₃alkyl-,═N—O—C₁-C₈alkyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkenyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkynyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkenyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkynyl-, —C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-C₂-C₄alkenyl-, —C₀-C₃alkyl-aryl-C₂-C₄alkynyl-,—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heteroaryl-C₁-C₃alkenyl-,—C₀-C₃alkyl-heteroaryl-C₁-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-heteroaryl-C₂-C₆alkenyl-, and —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-heteroaryl-C₂-C₆alkenyl-, wherein each alkyl,alkenyl, aryl, alkynyl, heteroaryl and heterocyclyl moiety is optionallysubstituted; and wherein the bridge is methylene or propylene;provided that Formula (I) excludes those compounds wherein-Q-J-L-C(O)Z is optionally substituted—C₁-C₁₃alkyl-N(R³)—C₀-C₆alkyl-aryl-C₂alkenyl-C(O)NHOH; and

is selected from the group consisting of aromatic polycycles,non-aromatic polycycles, mixed aryl and non-arylpolycycles,polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl andnon-aryl polyheterocycles, each of which is optionally substituted;andprovided that Formula (I) excludes compounds of Formula (A)

wherein R⁹⁰⁶ is selected from the group consisting of aryl andheteroaryl;T⁹⁰⁶ is selected from the group consisting of—C₀₋₆alkyl-S(O)₂—C₀₋₆alkyl-, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl- and C₁₋₃alkyl,wherein T⁹⁰⁶ is substituted at the carbon atom attached to R⁹⁰⁶ with amoiety selected from the group consisting of; aryl, heteroaryl,cycloalkyl and heterocycle;A⁹⁰⁶ is an optionally substituted unbridged heterocycle;Q⁹⁰⁶ is a bond;Het is an optionally substituted 5-membered aryl ring;L⁹⁰⁶ is a bond or —C₁₋₄alkyl-; andR^(906a) is —N(R^(906b))OH, wherein R^(906b) is selected from the groupconsisting of H, optionally substituted alkyl and optionally substitutedaryl;andprovided that Formula (I) excludes those compounds wherein-Q-J-L-C(O)Z is optionally substituted—C₀-C₄alkyl-X—C₁-C₄alkyl-phenyl-C₂alkenyl-C(O)NHOH;

is a 5- or 6-membered aromatic heterocyclic group condensed with acarbon ring or other heterocyclic ring, which

is substituted with 1 to 4 substituents selected from phenyl, another 5-or 6-membered aromatic heterocyclic group and a heterocyclic group, saidheterocyclic group being optionally substituted with C₁₋₄alkyl, a benzylgroup or a pyridylmethyl group; andX is a moiety having a structure selected from the group consisting of—C(O)N(R^(A1))—, —O—C(O)—N(R^(A1))—, —SO₂—, —N(R^(A2))SO₂—, whereinR^(A1) and R^(A2) are independently —H or optionally substitutedC₁-C₄alkyl;andprovided that Formula (I) excludes compounds wherein B-Q- is

-J-L- is

wherein R is directly attached or attached through a linker, and isselected from the group consisting of substituted or unsubstituted aryl,cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino,9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranchedalkyl, alkenyl, alkyoxy, aryloxy, arylalkyloxy and pyridine group,wherein the linker is selected from the group consisting of an amidemoiety, —O—, —S—, —NH— and —CH₂—; andprovided that Formula (I) excludes compounds of Formula (B)

whereinR^(B) is H or phenyl;A^(B) is a bi- or tricyclic residue optionally partially or totallyunsaturated, and which optionally contains one or more heteroatomsselected from the group consisting of N, S and O, and optionallysubstituted by hydroxy, alkanoyloxy, primary, secondary or tertiaryamino, aminoC₁-C₄alkyl, mono- or di(C₁-C₄)alkyl-aminoC₁-C₄alkyl,halogen, C₁-C₄alkyl and tri(C₁-C₄)alkylammoniumC₁-C₄alkyl;

is a chain of 1 to 5 carbon atoms optionally containing a double bond oran NR group, wherein R is H or C₁-C₄alkyl;X^(B) is absent, an oxygen atom or an NR group, wherein R is H orC₁-C₄alkyl; andB^(B) is a phenylene or cyclohexylene ring;andprovided that Formula (I) excludes compounds of Formula (D)

whereinA^(D) is selected from the group consisting of a 4- to 10-memberedaromatic or non-aromatic heterocyclyl;

X^(D) is C═O or S(O)₂;

R^(D1) is H or C₁-C₆alkyl;R^(D2) is independently selected from the group consisting of oxo,(C═O)—NH₂, C₁-C₆alkyl-aryl and heterocyclyl, when A^(D) is anon-aromatic heterocycle, wherein said alkyl, and aryl moieties areoptionally substituted with one to three R^(b); orR^(D2) is independently selected from the group consisting of OH, NO₂,(C═O)₀₋₁—O₀₋₁—C₁-C₆alkyl, CN, (C═O)₀₋₁—O₀₋₁—C₃-C₁₀cycloakyl, halogen,(C═O)₀₋₁—N(R³)₂, CF₃, NH—S(O)₀₋₂—R³, (C═O)₀₋₁—O₀₋₁-heterocyclyl,(C═O)₀₋₁—O₀₋₁-aryl, S(O)₀₋₂—R^(w), NH(C═O)R^(a), C₁-C₆alkyl-aryl andheterocyclyl, when A^(D) is an aromatic heterocyclyl, wherein saidalkyl, cycloalkyl, aryl and heterocyclyl are optionally substituted withone to three R^(b);R^(a) is independently H or C₁-C₆alkyl; andR^(b) is independently selected from the group consisting of oxo, NO₂,N(R^(a))₂, OH, CN, halogen, CF₃ and C₁-C₆alkyl;andprovided that Formula (I) excludes compounds of Formula (E)

whereinA^(E) is selected from the group consisting of —CH₂—O—, —CH₂—S—,—CH₂—CH₂— and —NH—CO—;X^(E) is selected from the group consisting of —N(R^(E3))—, ═C(O) and—CH(OH)—;Y^(E) is selected from the group consisting of O, S and —N(R^(E4))—;Z^(E) is selected from the group consisting of a straight chainC₄-C₈alkylene, wherein one CH₂ group may be replaced by an oxygen or asulfur atom, or wherein 2 carbon atoms form a C═C double bond, and whichis either unsubstituted or substituted by one or two substituentsselected from C₁-C₄alkyl and halogen;R^(E1) and R^(E2) are independently selected from the group consistingof H, halogen, C₁-C₄alkyl, trifluoromethyl, hydroxy, C₁-C₄alkoxy,benzyloxy, C₁-C₃alkylenedioxy, nitro, amino, C₁-C₄alkylamino,di[(C₁-C₄)alkyl]-amino, and C₁-C₄alkanoylamino; andR^(E1) and R^(E2) are independently selected from H and C₁-C₄alkyl; andprovided that Formula (I) excludes compounds of Formula (F)

A^(F)-Q^(1F)-J^(F)-Q^(2F)-C(O)—NH—OH  (F)

whereinA^(F) is a C₅-C₂₀ aryl group or a 5-20 membered heteroaryl group, eachhaving one ring or two or more fused rings, wherein at least one ring isaromatic, said ary and heteroaryl groups being optionally substituted;Q^(1F) is a linker group having a backbone length of at least 2 carbonatoms, the linker being optionally substituted;

J^(F) is —N(R^(F))—C(O)— or —C(O)—N(R^(F))—;

Q^(2F) is selected from the group consisting of C₁-C₁₀alkyl, C₅-C₂₀aryl,5 to 20 membered heteroaryl, C₅-C₂₀aryl-C₁-C₁₀alkyl, 5 to 20 memberedheteroaryl-C₁-C₁₀alkyl, C₁-C₁₀alkyl-C₅-C₂₀aryl and C₁-C₁₀alkyl-5 to 20membered heteroaryl, each of which is optionally substituted; andR^(F) is selected from the group consisting of H, C₁-C₇alkyl,C₃-C₂₀heterocyclyl and C₅-C₂₀aryl, each of which is optionallysubstituted; andprovided that Formula (I) excludes compounds wherein

Z is —N(R¹)(OR²);

R¹ and R² are independently selected from the group consisting of H,C₁-C₆alkyl, aryl and heteroaryl;L is a bond; and

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, heterocyclyl, cycloalkyl,heterocyclyl-alkyl, cycloalkyl-alkyl, C₁-C₁₀alkyl,(aryl)₂-CH—C₀-C₆alkyl-, (aryl)(heteroaryl)CH—C₀-C₆alkyl- and(heteroaryl)₂CH—C₀-C₆alkyl-, each of which is optionally substituted;andQ comprises a ring selected from the group consisting of

wherein Y^(F) is nitrogen or —CH<, and Z^(F) is oxygen, NH or —CH₂— ifZ^(F) is not bonded to

or Z^(F) is nitrogen or —CH< if Z^(F) is bonded to

through a covalent bond or a radical group selected from the groupconsisting of H, —C(R¹)(R²)—, —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-,—C₁-C₈alkyl-, —C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C(R¹)(R²)—N(R³)—C(O)—C₀-C₃alkyl-, —C(R¹)(R²)—C(O)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-, —C(R¹))(R²)—O—C(O)—C₀-C₃alkyl-,—C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-,—C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,—C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond,(R³)(R^(3a))N—C₂-C₄alkyl-, —O—C₂-C₄alkyl-, and R³—O—C₂-C₄alkyl-;or

is selected from the group consisting of b-53, b-62 (wherein D³ is

b-69 (wherein R⁴ is H), b-70, b-72 (wherein D³ is

b-96 and b-93; andQ-J is selected from the group consisting of—X^(F)—C₀₋₄alkyl-aryl-C₀₋₄alkyl-,—X^(F)—C₀₋₄alkyl-heteroaryl-C₀₋₄alkyl-, and—X^(F)—C₀₋₄alkyl-heterocyclyl-C₀₋₄alkyl-, wherein said alkyl, aryl,heteroaryl, and heterocyclyl are optionally substituted, and whereinsaid heterocyclyl is a mono- or bi-saturated or mono- or bi-unsaturatedheterocyclic ring, and whereinX^(F) is selected from the group consisting of

wherein the left side attaches to

and wherein r and s are each independently 0, 1, 2, 3, 4 or 5, wherein rand s cannot be both 0 and when r or s are 0 then a direct bound inintended; each r′ is independently 0, 1, 3, 3 or 4 and r′ cannot be 0when s is 0; R^(4A) is H, C₁₋₆alkyl or phenyl;Y^(F) is nitrogen or —CH<, and Z^(F) is oxygen, NH or —CH₂— if Z^(F) isnot bonded to

or Z^(F) Y^(F) is nitrogen or —CH< if Z^(F) is bonded to

and provided that Formula (I) excludes those compounds having thefollowing structure:

whereinX⁹ is selected from the group consisting of CO, SO₂ and CH₂;Y⁹ is selected from the group consisting of N—R^(9f), CH—OR^(9f),CH—NR^(9f)R^(9i) and C═CH—CO—R^(9g);A⁹ and B⁹ are independently selected from 5- or 6-membered rings;R^(9a), R^(9b), R^(9c) and R^(9d) are independently selected from thegroup consisting of H, halogen, CF₃, NO₂, NR^(9i)R^(9j), CN, COOH,(CH₂)₀₋₂—CONR^(9i)R^(9j), C₁₋₆alkyl, OH, O—C₁₋₆alkyl, O-cyclopropyl,O—(CH₂)₂—O—C₁₋₆alkyl, O—(CH₂)₂—NR^(9i)R^(9j), O—CONHR^(9i),CH₂-Z⁹-R^(9h), COR^(9i), CR^(9i)R^(9m)R^(9n), SR^(9i), SO₂R^(9o),CR^(9i)NOR^(9i), CR^(9i)NNR^(9i)R⁹j, a Q⁹-(CH₂)₂₋₉CONHOH group, furan,thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole,isothiazole, 1,2,3-oxathiazole, 1,2,3-triazole, pyridine, pyridazine,pyrimidine, pyrazine, morpholine thiomorpholine, piperidine andpyrrolidine;

R^(9e) and R^(9f) are Q^(9a)-(CH₂)₂₋₉CONHOH; R^(9g) isNH—(CH₂)₂₋₉CONHOH;

R^(9h) is a (CH₂)P—R^(9k) group, wherein R^(9k) can be methyl orhydroxyl;Z⁹ is selected from the group consisting of O, NR^(9L) and S;Q⁹ is selected from the group consisting of a chemical bond, —O—, —S—,—NR^(9L)—, —NR^(9i)CO—, —CONR^(9i)—, —W⁹—, —COW⁹—, wherein W⁹ ispiperidine or pyrrolidine;Q^(9a) is a bond or a —CO—;R^(9a) and R^(9j) are independently H or a C₁₋₆alkyl;

R^(9L) is H or R^(9h);

R^(9m) and R^(9n) can either be a fluorine atom or oxygen atoms linkedtogether by an alkyl chain consisting of 2 or 3 CH₂; andR^(9o) is a C₁₋₆alkyl; provided that (1) only one (CH₂)₂₋₉CONHOH ispresent in the molecule and (2) when X⁹ is CO and A⁹ and B⁹ are bothbenzene then R^(9c) and R^(9d) cannot signify Q⁹-(CH₂)₂₋₉CONHOH.

In a preferred embodiment of the present invention,

are independently selected from the group consisting of phenyl,heteroaryl and heterocyclyl, wherein each phenyl, heteroaryl andheterocyclyl is optionally substituted with one to three substituentsindependently selected from the group consisting of halo, —CF₃, —OCF₃,—NO₂, —CN, —C₁-C₆alkyl, —C₁-C₆alkoxyl, —O—C₂-C₆alkyl-O—R⁵³, —O—R⁵³,—C₀-C₆alkyl-S(O)₀₋₂—R⁵³, —C₀-C₆alkyl-C(O)—R⁵³, —C₀-C₆alkyl-C(O)NR⁵⁰R⁵¹,—C₀-C₆alkyl-NR⁵²C(O)—R⁵³, —C₀-C₆alkyl-S(O)₂NR⁵⁰R⁵¹,—C₀-C₆alkyl-NR⁵²S(O)₂—R⁵³, —C₀-C₆alkyl-OC(O)NR⁵⁰R⁵¹,—C₀-C₆alkyl-NR⁵²C(O)O—R⁵³, —C₀-C₆alkyl-NR⁵²C(O)NR⁵⁰R⁵¹,—C₀-C₆alkyl-C(O)O—R⁵³, —C₀-C₆alkyl-OC(O)—R⁵³, —C₀-C₆alkyl-aryl,—C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-C₃-C₇cycloalkyl,—C₀-C₆alkyl-heterocyclyl, —C₀-C₆alkyl-NR⁵⁰R⁵¹, —O—C₂-C₆alkyl-NR⁵⁰R⁵¹,—NR⁵³—C₂-C₆alkyl-NR⁵⁰R⁵¹ and —O-heterocyclyl-R⁵³.

In a preferred embodiment of the present invention,

are independently selected from the group consisting of phenyl,heteroaryl and heterocyclyl, wherein each phenyl, heteroaryl andheterocyclyl is optionally substituted with one to three substituentsindependently selected from the group consisting of R⁴

In a preferred embodiment of the compounds of the present invention, J-Qis selected from the group consisting of —C₁-C₉alkyl, —C₁-C₉heteroalkyl,phenyl, aryl, heteroaryl, —C₁-C₄alkyl-phenyl, —C₁-C₄alkyl-aryl,—C₁-C₄alkyl-heteroaryl, —NR³³aryl, —NR³³—C₁-C₄alkyl-aryl,—NR³³heteroaryl and NR³³—C₁-C₄alkyl-heteroaryl, wherein each alkyl andheteroalkyl is optionally substituted with one or three substituentsindependently selected from the group consisting of F, —OH and oxo, andwherein each phenyl, aryl and heteroaryl is optionally substituted withone or two substituents independently selected from the group consistingof halo, —OH, —OR⁵³, —C₁-C₄alkyl, —C₁-C₄alkoxyl,—O—C₂-C₄alkyl-O—C₁-C₆alkyl, —CN, —CF₃, —OCF₃, —NO₂,—C₁-C₆alkyl-S(O)₀₋₂R⁵³, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ and—N(C₁-C₆alkyl)₂, wherein R³³ is independently selected from the groupconsisting of —H, —C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₇cycloalkyl and—C₀-C₄alkyl-phenyl, wherein each phenyl and cycloalkyl is optionallysubstituted with one or three substituents independently selected fromthe group consisting of halo, —OH, —NO₂, —CF₃, —OCF₃, amino,—N(C₁-C₆alkyl)₂, —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —C₁-C₄alkoxyl-CN,—O—C₂alkyl-O—CH₃, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ or —C₁-C₄alkyl.

In a preferred embodiment, embodiment A, of the compounds of the presentinvention, Q comprises a bridged heterocycle,

comprises a first ring structure, said first ring structure attached viaa covalent bond to said bridged heterocycle and J comprises a secondring structure, said second ring structure attached via a covalent bondto said bridged heterocycle, each of which is optionally substituted. Inanother preferred embodiment, L is a covalent bond.

In another preferred embodiment, embodiment B, of the compoundsaccording to the present invention, L is a covalent bond, Q is aheterocycle comprising a one or three carbon bridge, and J isheteroaryl, wherein each of

Q and J are optionally substituted.

In another preferred embodiment, embodiment B-2, of the compoundsaccording to the present invention, L is a covalent bond, Q comprises aheterocycle comprising an unsubstituted methylene, ethylene or propylenebridge, and J is heteroaryl, wherein each of

Q and J are otherwise optionally substituted.

In another preferred embodiment, embodiment B-3, of the compoundsaccording to the present invention, L is a covalent bond, Q comprises aheterocycle comprising an unsubstituted methylene, ethylene or propylenebridge, and J is aryl, wherein each of

Q and J are otherwise optionally substituted.

In another preferred embodiment, embodiment C, of the compoundsaccording to the present invention, L is a covalent bond, Q is aheterocycle comprising a one or three carbon bridge, and J ispryimidine, wherein each of

Q and J are optionally substituted.

In another preferred embodiment, embodiment D, of the compoundsaccording to the present invention, L is a covalent bond, Q is aheterocycle comprising an unsubstituted methylene bridge, and J ispryimidine, wherein each of

Q and J are otherwise optionally substituted.

In another preferred embodiment, embodiment E, of the compoundsaccording to the present invention, L is a covalent bond, Q is aheterocycle comprising a three carbon bridge; and J is pryimidine,wherein each of

Q and J are optionally substituted.

In another preferred embodiment, embodiment F, of the compoundsaccording to the present invention, L is a covalent bond, Q is a2,5-diazabicyclo[2.2.1]heptane, and J is pryimidine, wherein each of

Q and J are optionally substituted.

In a preferred embodiment, embodiment G, of each of the forgoing,

is an optionally substituted aryl or heteroary, preferably aryl, morepreferably phenyl.

In another preferred embodiment, embodiment G-1, of each of theembodiments A to F,

is an optionally substituted heteroary, preferably pyridine.

In a preferred embodiment, embodiment H, of the compounds of the presentinvention,

is a radical selected from the group consisting of

In another preferred embodiment, embodiment I, of the compoundsaccording to the present invention,

is a radical selected from the group consisting of

wherein when

is attached via

and wherein when

Q is attached via D¹-D².

In another preferred embodiment, embodiment J, of the compoundsaccording to the present invention

is a radical selected from the group consisting of

In another preferred embodiment, embodiment K, of the compoundsaccording to the present invention, Q is an optionally substitutedmoiety selected from the group consisting of

or where possible, an (R,R) or (S,S) enantiomer or a mixture ofenantiomers, preferably an (R,R) enantiomer, more preferably an (S,S)enantiomer thereof, wherein G and G¹ are independently selected from—CH— and N; w1 and w2 are independently 0, 1, 2 or 3, provided that whenboth G and G¹ are N, then w1 and W2 are independently 1, 2 or 3; andwherein each ring structure includes a 0 (i.e., a bond), 1, 2 or 3carbon bridge between two non-adjacent carbon atoms, provided that

is absent when U¹ is H, N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-.Preferrably the ring size is 6, 7, 8 or 9 ring atoms, excluding anybridge atoms.

In another preferred embodiment, embodiment L, of the compoundsaccording to the present invention, Q is an optionally substitutedmoiety selected from the group consisting of

or where possible, an (R,R) or (S,S) enantiomer or a mixture ofenantiomers, preferably an (R,R) enantiomer, more preferably an (S,S)enantiomer thereof, wherein w1 and w2 are independently 0, 1, 2 or 3,provided that when the ring includes two N atoms, then w1 and w2 areindependently 1, 2 or 3; and wherein each ring structure includes a 0(i.e., a bond), 1, 2 or 3 carbon bridge between two non-adjacent carbonatoms, provided that

is absent when U¹ is H, N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-.

In another preferred embodiment, embodiment M, of the compoundsaccording to the present invention, Q is an optionally substitutedmoiety, selected from the group consisting of

or wherein possible, a (R,R) or (S,S) enantiomer or a mixture ofenantiomers, preferably an (R,R) enantiomer, more preferably an (S,S)enantiomer thereof, wherein n is 1, 2 or 3, and wherein

is absent when Q is structure (a-1), (a-2), (a-3) or when U¹ is H,N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-.

In another preferred embodiment, embodiment N, of the compoundsaccording to the present invention, Q is an optionally substitutedmoiety selected from the group consisting of

or wherein possible, a (R,R) or (S,S) enantiomer or a mixture ofenantiomers, preferably an (R,R) enantiomer, more preferably an (S,S)enantiomer thereof, wherein

is absent when U¹ is H, N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-.

In a preferred embodiment, embodiment 0, of the compounds of the presentinvention,

-   Z is —N(R¹)(OR²);-   L is a covalent bond;-   J is selected from the group consisting of a covalent bond, ═CH—,    —C₁-C₈alkyl-, —C₀-C₃alkyl-C₁-C₈heteroalkyl-C₀-C₃alkyl-,    —C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃alkyl-,    —C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl-, —C₀-C₆alkyl-aryl-C₀-C₆alkyl-,    —C₀-C₆alkyl-aryl-C₂-C₆heteroalkyl-,    —C₀-C₆alkyl-cycloalkyl-C₀-C₆alkyl-,    —C₄-C₆heterocyclyl-aryl-C₀-C₆alkyl-,    —C₄-C₆heterocyclyl-aryl-C₀-C₆heteroalkyl-,    —C₀-C₆alkyl-C₄-C₆heterocyclyl-C₀-C₆alkyl-,    —C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-,    —C₀-C₆alkyl-heteroaryl-C₀-C₆heteroalkyl-,    —C₄-C₆heterocyclyl-heteroaryl-C₀-C₆alkyl-,    —C₀-C₆alkyl-aryl-C₂-C₆alkynyl-,    —C₀-C₆alkyl-heteroaryl-C₂-C₆alkynyl-,    —C₀-C₆alkyl-aryl-C₂-C₆alkynyl-C₂-C₆alkenyl-,    —C₀-C₆alkyl-aryl-C₂-C₆alkenyl-,    —C₀-C₆alkyl-heteroaryl-C₂-C₆alkenyl-,    —C₂-C₆alkenyl-aryl-C₀-C₆alkyl-,    —C₂-C₆alkenyl-heteroaryl-C₀-C₆alkyl-,    —C₀-C₆alkylaryl-aryl-C₀-C₆alkyl-,    —C₀-C₆alkylaryl-heteroaryl-C₀-C₆alkyl- and    —C₀-C₆alkyl-C₃-C₆cycloalkyl-C₀-C₆alkyl-, wherein each alkyl,    alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, and    cycloalkyl moiety is optionally substituted, wherein when J is ═CH—,    Q is a covalent bond and B is attached through a carbon sp² to J;-   Q is a moiety selected from the group consisting of

-   or an optionally substituted (R,R) or (S,S) enantiomer or a mixture    of enantiomers, preferably an (R,R) enantiomer, more preferably an    (S,S) enantiomer thereof, wherein n is 0, 1, 2 or 3; and-   U is selected from the group consisting of    —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-, —C₁-C₈alkyl-,    —C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-,    —C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-,    —C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,    —C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond and    —O—C₂-C₄alkyl-; and-   U¹ is selected from the group consisting of H,    —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-, —C₁-C₈alkyl-,    —C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-,    —C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-,    —C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,    —C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond,    (R³)(R^(3a))N—C₂-C₄alkyl-, —O—C₂-C₄alkyl-, and R³—O—C₂-C₄alkyl-;-   wherein

is absent when Q is structure (a-1), (a-2), (a-3) or when U¹ is H,N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-.

In a preferred embodiment of embodiment 0, embodiment 0-1, of thecompounds according to the present invention, J is selected from thegroup consisting of a —C₀-C₃alkyl-C₁-C₈heteroalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-aryl-C₂-C₆heteroalkyl-,—C₀-C₆alkyl-cycloalkyl-C₀-C₆alkyl-, —C₄-C₆heterocyclyl-aryl-C₀-C₆alkyl-,—C₄-C₆heterocyclyl-aryl-C₀-C₆heteroalkyl-,—C₀-C₆alkyl-C₄-C₆heterocyclyl-C₀-C₆alkyl-,—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkyl-heteroaryl-C₀-C₆heteroalkyl-,—C₄-C₆heterocyclyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkynyl-, —C₀-C₆alkyl-heteroaryl-C₂-C₆alkynyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkynyl-C₂-C₆alkenyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-heteroaryl-C₂-C₆alkenyl-,—C₂-C₆alkenyl-aryl-C₀-C₆alkyl-, —C₂-C₆alkenyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkylaryl-aryl-C₀-C₆alkyl-, —C₀-C₆alkylaryl-heteroaryl-C₀-C₆alkyl-and —C₀-C₆alkyl-C₃-C₆cycloalkyl-C₀-C₆alkyl-, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, andcycloalkyl moiety is optionally substituted.

In a preferred embodiment of embodiment 0-1, embodiment 0-2, J is—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl- or —C₀-C₆alkyl-aryl-C₀-C₆alkyl-.

In a preferred embodiment of embodiment 0-2, embodiment 0-3, Q isselected from the group consisting of

In a preferred embodiment of embodiment 0-3, embodiment 0-4, U and U¹are a covalent bond.

In a preferred embodiment of embodiment 0-3 embodiment 0-5, U and U¹ are—C(O)—.

In another preferred embodiment of embodiment 0-3, embodiment 0-6,moiety U is —C(O)—O—C₀-C₃alkyl-.

In another preferred embodiment of embodiment 0-3, embodiment 0-7, U¹ is—C₀-C₃alkyl-O—C(O)—.

In another preferred embodiment, embodiment P of the compounds accordingto the present invention

-   J is selected from the group consisting of —C₁-C₈alkyl-,    —C₀-C₆alkyl-aryl-C₀-C₃alkyl-C₂alkenyl-C₀-C₃alkyl,    —C₀-C₆alkyl-heteroaryl-C₀-C₃alkyl-C₂alkenyl-C₀-C₃alkyl,    —C₀-C₆alkyl-aryl-C₀-C₆alkyl- and —C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-,    wherein each is optionally substituted;-   Q is selected from the group consisting of a covalent bond,    —C₁-C₈alkyl-, ═N—O—, —C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-,    —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C₀-C₆alkyl-C(O)—C₀-C₃alkyl-,    —C₀-C₆alkyl-O—C₀-C₃alkyl-, —C₀-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-,    —C₀-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-,    —C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl-, wherein each alkyl and    heterocyclyl moiety is optionally substituted;    or-   Q is selected from the group consisting of:

wherein

-   U¹ is selected from the group consisting of    —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-, —C₁-C₈alkyl-,    —C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl- and a covalent bond;-   wherein, when B is attached to Q via a N in B, then Q is selected    from the group consisting of a covalent bond, —C(O)—C₁-C₃alkyl-O—,    —C₁-C₈alkyl-, —C₀-C₆alkyl-C(O)—C₀-C₃alkyl-,    —C₂-C₆alkyl-O—C₀-C₃alkyl-, —C₁-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl- and    —C₁-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-, wherein each alkyl moiety is    optionally substituted;    provided that

is absent when Q is

and

is selected from the group consisting of hydrogen, aryl, cycloalkyl,heterocyclyl, heteroaryl, heteroarylalkyl, aryl-alkyl-,(heteroaryl)₂-CH—C₀-C₆alkyl- and (aryl)₂-CH—C₀-C₆alkyl-, each of whichis optionally substituted, provided that Q is

or

is a radical selected from the group consisting of

In a preferred embodiment of embodiment P, embodiment P-1,

In another preferred embodiment, embodiment Q, of the compoundsaccording to the present invention, the compound has a structureselected from the group consisting of

wherein k is 0 or 3.

In another preferred embodiment, embodiment R, of the compoundsaccording to the present invention, Z is —NR¹OR², R¹ and R² are H, and Lis a covalent bond.

In another preferred embodiment, embodiment S, of the compoundsaccording to the present invention, Z is H and L is —N(OH).

In another preferred embodiment, embodiment T, of the compoundsaccording to the present invention, J is selected from the groupconsisting of —C₁-C₈alkyl-, —C₀-C₃alkyl-C₁-C₈alkenyl-C₀-C₃-alkyl,—C₀-C₆alkyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-aryl-C₂-C₆alkenyl,—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl- and—C₀-C₆alkyl-heterocyclyl-heteroaryl-C₀-C₆alkyl-.

In another preferred embodiment, embodiment U, of the compoundsaccording to the present invention, J is selected from the groupconsisting of

In another preferred embodiment, embodiment V, of the compoundsaccording to the present invention, Q is selected from the groupconsisting of a covalent bond, —C₁-C₈alkyl-, ═N—O—,—C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-C(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-O—C₀-C₃alkyl-,—C₀-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-, —C₀-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₄alkyl-,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C₀-C₆alkyl-SO₂—N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—SO₂—C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-S—C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl-, —C₀-C₃alkyl-C═N—O—C₀-C₃alkyl-,-heterocyclyl-C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C(O)—C₀-C₆alkyl-bridgedheterocyclyl-C₀-C₃alkyl-,—N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-SO₂—N(R³)—, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,heterocyclyl and alkenyl moiety is optionally substituted.

In another preferred embodiment, embodiment W, of the compoundsaccording to the present invention, Q is selected from the groupconsisting of covalent bond, ═N—O—, —C₁-C₈ alkyl-, —C₀-C₆alkyl-N(R₃)—C₀-C₃ alkyl-, —C₀-C₆ alkyl-C(O)—C₀-C₃ alkyl-, —C₀-C₆alkyl-C(O)NR₃—C₀-C₃ alkyl-, —C₀-C₆ alkyl-O—C₀-C₃ alkyl- and—C₀-C₃alkyl-heterocyclyl-C₀-C₃-alkyl.

In another preferred embodiment, embodiment X, of the compoundsaccording to the present invention, Q is selected from the groupconsisting of

In another preferred embodiment, embodiment Y, of the compoundsaccording to the present invention,

is selected from the group consisting of aryl, aryl-alkyl-, heteroaryl,heteroaryl-alkyl-, (aryl)₂-CH—C₀-C₆alkyl-,(aryl)(heteroaryl)CH—C₀-C₆alkyl-, (heteroaryl)₂CH—C₀-C₆alkyl- and(aryl)₂-CH—C₀-C₆alkyl-C(O)—, -wherein each group is optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromthe group consisting of hydroxy, amino, halo, C₁-C₆alkyl, nitro, cyano,C₂-C₆alkoxy, C₁-C₆alkylamino and CF₃.

In another preferred embodiment, embodiment Z, of the compoundsaccording to the present invention,

is selected from the group consisting of

In another preferred embodiment, embodiment AA, of the compoundsaccording to the present invention, each alkyl, alkenyl, alkynyl,heteroalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl moiety of Jis optionally substituted with from one to three substituentsindependently selected from the group consisting of alkyl, heterocyclyl,C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl andheteroaryl.

In another preferred embodiment, embodiment BB, of the compoundsaccording to the present invention, Q is selected from the groupconsisting of a covalent bond, —C₁-C₈alkyl-, ═N—O—,—C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-C(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-O—C₀-C₃alkyl-,—C₀-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-, —C₀-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₄alkyl-,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C₀-C₆alkyl-SO₂—N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—SO₂—C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-S—C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl-, —C₀-C₃alkyl-C═N—O—C₀-C₃alkyl-,-heterocyclyl-C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C(O)—C₀-C₆alkyl-bridgedheterocyclyl-C₀-C₃alkyl-,—N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-SO₂—N(R³)—, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,heterocyclyl and alkenyl moiety is optionally substituted with from oneto three substituents independently selected from the group consistingof alkyl, heterocyclyl, C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹,heteroalkyl, heteroaryl, C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂,—C₃-C₆cycloalkyl, -alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl,alkylheteroaryl and heteroaryl.

In another preferred embodiment, embodiment CC, of the compoundsaccording to the present invention, Q is an optionally substituted(1R,4R) or (1S,4S) 2,5-diazabicyclo[2.2.1]heptane enantiomer or amixture of enantiomers, preferably an (1R,4R) enantiomer, morepreferably an (1S,4S) enantiomer, selected from the group consisting of

or

Q is

is absent; or

Q is

is H.

In another preferred embodiment, embodiment DD, of the compoundsaccording to the present invention, when

is attached to Q via a N in

then Q is selected from the group consisting of —C₁-C₈alkyl-,—C₂-C₆alkyl-N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-C(O)—C₀-C₃alkyl-, —C₂-C₆alkyl-O—C₀-C₃alkyl-,—C₁-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-, —C₁-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-,—C₂-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl,—C₂-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₃alkyl,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C(O)—O—C₀-C₄alkyl,—C₀-C₆alkyl-S(O)₂—N(R³)—C₀-C₃alkyl, —C₂-C₆alkyl-N(R³)—S(O)₂—C₀-C₃alkyl,—C₂-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₂-C₆alkyl-S—C₀-C₃alkyl,—C₂-C₆alkyl-S(O)—C₀-C₃alkyl, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl,—C₂-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl, —C₂-C₃alkyl-C═N—O—C₀-C₃alkyl,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-S(O₂)—N(R³)—,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,heterocyclyl and alkenyl moiety is optionally substituted with from oneto three substituents independently selected the group consisting ofalkyl, heterocyclyl, C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹,heteroalkyl, heteroaryl, C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂,—C₃-C₆cycloalkyl, -alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl,alkylheteroaryl and heteroaryl, and wherein the heterocyclyl moietyoptionally has a bridge of —(CH₂)₀₋₃—.

In another preferred embodiment, embodiment EE, of the compoundsaccording to the present invention, each R₃ is independently selectedfrom the group consisting of —H, alkyl, heterocyclyl, C₂-C₆alkenyl,C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl,heteroaryl and a covalent bond, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety isoptionally substituted with from one to three substituents independentlyselected from the group consisting of alkyl, heterocyclyl, C₂-C₆alkenyl,C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl andheteroaryl.

In another preferred embodiment, embodiment FF, of the compoundsaccording to the present invention, Q-J-L is selected from the groupconsisting of —C₃-C₈alkyl-, —C(O)—C₃-C₈alkyl-,—C₀-C₃alkyl-O—C₃-C₈alkyl-, —C₀-C₃alkyl-C₁-C₄alkenyl-C₀-C₃alkyl-,═N—O—C₁-C₈alkyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkenyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkynyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkenyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkynyl-, —C₀-C₃alkyl-aryl-,—C₀-C₃alkyl-aryl-C₀-C₃alkyl-, —C₀-C₃alkyl-aryl-C₂-C₄alkenyl-,—C₀-C₃alkyl-aryl-C₂-C₄alkynyl-, —C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₁-C₃alkyl-heteroaryl-C₁-C₃alkenyl-,—C₁-C₃alkyl-heteroaryl-C₁-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl- and—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-, wherein each alkyl,alkenyl, aryl, alkynyl, heteroaryl and heterocyclyl moiety is optionallysubstituted with from one to three substituents independently selectedfrom the group consisting of alkyl, heterocyclyl, C₂-C₆alkenyl,C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl andheteroaryl.

In another preferred embodiment, embodiment GG, of the compoundsaccording to the present invention,

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, (aryl)₂-CH—C₀-C₆alkyl-,(aryl)(heteroaryl)CH—C₀-C₆alkyl-, (heteroaryl)₂CH—C₀-C₆alkyl- and(aryl)₂-CH—C₀-C₆alkyl-C(O)—, each of which is optionally substitutedwith from one to three substituents independently selected from thegroup consisting of alkyl, heterocyclyl, C₂-C₆alkenyl, C₂-C₃alkynyl,C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl, C₀-C₆alkylheteroaryl, C(O)CF₃,—C(O)—NH₂, —C₃-C₆cycloalkyl, -alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl,aryl, alkylheteroaryl and heteroaryl, provided that variable n of Q is0, 1 or 3.

In another preferred embodiment, embodiment HH,

is selected from the group consisting of structures (b-1) to (b-121) andQ-J-L taken together is selected from the group consisting of—C₃-C₈alkyl-, —C(O)—C₃-C₈alkyl-, —C₀-C₃alkyl-O—C₃-C₈alkyl-,—C₀-C₃alkyl-C₁-C₄alkenyl-C₀-C₃alkyl-, ═N—O—C₁-C₈alkyl-,═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkenyl-,═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkynyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkenyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkynyl-, —C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-C₂-C₄alkenyl-, —C₀-C₃alkyl-aryl-C₂-C₄alkynyl-,—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heteroaryl-C₁-C₃alkenyl-,—C₀-C₃alkyl-heteroaryl-C₁-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-heteroaryl-C₂-C₆alkenyl-, and —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-heteroaryl-C₂-C₆alkenyl-, wherein each alkyl,alkenyl, aryl, alkynyl, heteroaryl and heterocyclyl moiety is optionallysubstituted; and wherein the bridge is methylene or propylene.

In another preferred embodiment, embodiment II, of the compoundsaccording to the present invention B-Q-J-L- are taken together, whereineach such B-Q-J-L group is optionally substituted with up to 4substituents independently selected from the group consisting ofhydroxy, amino, halo, C₁-C₆alkyl, nitro, cyano, C₂-C₆alkoxy, C₁-C₆aminoand CF₃, heterocyclyl, C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹,heteroalkyl, heteroaryl, C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂,—C₃-C₆cycloalkyl, -alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl andalkylheteroaryl.

In another preferred embodiment, embodiment JJ, of the compoundsaccording to the present invention, R⁴ is independently selected fromthe group consisting of —H, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkyl-R³, —C₀-C₆alkyl-OR³, —C₀-C₆alkyl-OR¹, —C₀-C₆alkyl-C(O)—OR³,—C₀-C₆alkyl-C(O)NR³R^(3a), —CH═CH—C(O)—OR³, —CH═CH—C(O)—N(R³)(R^(3a)),—N(R³)—C(O)—CF³, —N(R³)—C₂-C₆alkyl-N(R³)(R^(3a)),—C₀-C₆alkyl-N(R³)(R^(3a)), —N(R³)—C(O)—C₁-C₆alkyl-R³,—N(R³)—S(O)₂—C₁-C₆alkyl-R³, —S(O)₂—N(R³)R³, —O—C₂-C₆alkyl-N(R³)(R^(3a)),—S—R³, —S(O)—C₁-C₆alkyl-R³, —S(O)₂—C₁-C₆alkyl-R³, C₃-C₆cycloalkyl,heterocyclyl, C₄-C₇heterocyclyl-R³, —O—C₂-C₄alkyl-heterocyclyl,—O-heterocyclyl-C(O)—OR³, —O—C₀-C₄alkyl-aryl, —O—C₀-C₄alkyl-heteroaryl,—O—C(O)—NR³—C₀-C₄alkyl-aryl, —O—C(O)—NR³, —C₀-C₄alkyl-heteroaryl,—O—C₀-C₄alkyl-heterocyclylaryl, —O—C₀-C₄alkyl-heterocyclyl-heteroaryl,—N(R³)—C₂-C₄alkyl-heterocyclyl,—N(R³)C(O)N(R³)—C₀-C₄alkyl-heterocyclyl-R³, —C₀-C₄alkyl-OC(O)—R³,—C₀-C₄alkyl-N(R³)C(O)—O—R³, —C₀-C₄alkyl-heterocyclyl-C(O)—O—R³,—N(R³)—C₂-C₄alkyl-heterocyclyl, F, Cl, Br, I, NO₂, —CF₃, —SO₃H, —CN,—C₁-C₆ alkylaryl, aryl, heteroaryl, —C₁-C₆ alkylheteroaryl, wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroarylmoeity of the aformentioned R⁴ is optionally substituted with from oneto three substituents independently selected from the group consistingof alkyl, heterocyclyl, C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹,heteroalkyl, heteroaryl, C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂,—C₃-C₆cycloalkyl, -alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl,alkylheteroaryl and heteroaryl.

In another preferred embodiment, embodiment KK, of the compoundsaccording to the present invention, R^(3a) is independently selectedfrom the group consisting of —H, alkyl, heterocyclyl, C₂-C₆alkenyl,C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl andheteroaryl, covalent bond, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety isoptionally substituted with from one to three substituents independentlyselected from the group consisting of alkyl, heterocyclyl, C₂-C₆alkenyl,C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl andheteroaryl.

In another preferred embodiment, embodiment LL, of the compoundsaccording to the present invention, Q is selected from the groupconsisting of

or an optionally substituted (R,R) or (S,S) enantiomer or a mixture ofenantiomers, preferably an (R,R) enantiomer, more preferably an (S,S)enantiomer thereof, each of which is optionally substituted with asubstituent selected from the group consisting of halo, alkyl and aryl.

In another preferred embodiment, embodiment MM, of the compoundsaccording to the present invention,

is selected from the group consisting of

wherein

-   -M¹-M²- is —CH═CH— or —CH₂—CH₂—;-   A is selected from the group consisting of N, C(R⁴) and CH;-   Z is —NHOH;-   L is covalent bond;-   J is selected from the group consisting of —C₁-C₈alkyl-,    —C₀-C₆alkyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-aryl-C₂-C₆alkenyl-,    —C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl- and —CH═; and-   Q is selected from the group consisting of covalent bond, ═N—O—,    —C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl-    and —C₀-C₆alkyl-C(O)—C₀-C₃alkyl-.

In preferred embodiment of embodiment MM, embodiment MM-1,

is further selected from the group consisting of

In another preferred embodiment, embodiment NN, of the compoundsaccording

to the present invention,

is selected from the group consisting of

In another preferred embodiment, embodiment OO, of the compoundsaccording to the present invention,

is optionally substituted

W is —CH═CH— or —CH₂—CH₂—;

Y is selected from the group consisting of N, C(R⁴) and CH;

Z is —NHOH;

L is covalent bond;J is selected from the group consisting of —C₁-C₈alkyl-,—C₀-C₆alkyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-aryl-C₂-C₆alkenyl-,—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl- and —CH═; andQ is selected from the group consisting of covalent bond, ═N—O—,—C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl- and—C₀-C₆alkyl-C(O)—C₀-C₃alkyl-.

In another preferred embodiment, embodiment PP, of the compounds of thepresent invention,

is selected from the group consisting of

each of which is optionally substituted on a phenyl ring with one or twoR⁴;

Z is —NR¹OR² or H; R¹ and R² are —H;

L is covalent bond or —N(OH)—;J is —C₁-C₈alkyl-, —C₀-C₆alkyl-aryl-C₀-C₆alkyl-,—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkenyl-C₀-C₃alkyl-, —C₀-C₆alkyl-aryl-C₂-C₆alkenyl- and—C₂-C₆alkenyl-aryl-C₀-C₆alkyl-;Q is selected from the group consisting of covalent bond,—C₁-C₃alkyl-(C≡C)—C₀-C₃alkyl, —C₀-C₆alkyl-,—C₁-C₃alkyl-(CH═CH)—C₀-C₃alkyl-, —C₂-C₆alkyl-O—C₀-C₃alkyl-,—C₂-C₆alkyl-C(O)—C₀-C₃alkyl- and —C₂-C₆alkyl-heterocyclyl-C₀-C₃alkyl-;orQ is selected from the group consisting of a covalent bond,—C₁-C₃alkyl-(C≡C)—C₀-C₃alkyl, —C₀-C₆alkyl-,—C₁-C₃alkyl-(CH═CH)—C₀-C₃alkyl-, —C₀-C₆alkyl-O—C₀-C₃alkyl-,—C₀-C₆alkyl-C(O)—C₀-C₃alkyl- and —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-when

andR³ is H or cycloalkyl.

In another preferred embodiment, embodiment QQ, of the compoundsaccording to the present invention,

is selected from the group consisting of (aryl)₂-CH—C₀-C₆alkyl-,(aryl)₂-C₁-C₆alkyl- and (heteroaryl)₂-C₁-C₆alkyl-, wherein each aryl,alkyl and heteroaryl moiety is optionally substituted;

Z is NHOH;

Q is selected from the group consisting of—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-, ═N—O—,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl and —C₀-C₆alkyl-O—C₀-C₃alkyl;J is —C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl; andL is a covalent bond.

In another preferred embodiment, embodiment RR, of the compoundsaccording to the present invention,

is selected from the group consisting of aryl and (aryl)₂-alkyl, each ofwhich is optionally substituted and H;Q is selected from the group consisting of —C₀-C₆alkyl-bridgedheterocyclyl-C₀-C₃alkyl- and

J is —C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl;L is a covalent bond; and

Z is NHOH.

In another preferred embodiment, embodiment SS, of the compoundsaccording to the present invention,

Z is —NHOH;

R³ is H or alkyl;L is covalent bond;J is —C₁-C₈alkyl- or —C₀-C₃alkyl-C₁-C₈alkenyl-C₀-C₃alkyl-; andQ is covalent bond.

In another preferred embodiment, embodiment TT, of the compoundsaccording to the present invention,

Z is —NHOH;

L is a covalent bond;J is —C₁-C₈alkyl- or —C₀-C₆alkyl-aryl-C₂-C₆alkenyl-; andQ is a covalent bond.

In another preferred embodiment, embodiment UU, of the compoundsaccording to the present invention, the compound is selected from one ofthe following structures:

wherein R⁴ is as defined for embodiment (A), and A is selected from thegroup consisting of N and —CH═.

In another preferred embodiment, embodiment VV, of the compoundsaccording to the present invention, the compounds are represented by theFormula II:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs, polymorphs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof, whereinZ is selected from the group consisting of —N(R¹)OR² and H;L is selected from the group consisting of a covalent bond and —N(OR²)—;wherein, when L is —N(OR²)—, then Z is H; andwherein, when Z is H, then L is —N(OR²)—;R¹ and R² are independently selected from the group consisting of —H andC₁-C₆alkyl;W is nitrogen or carbon;D^(1a)-D^(2a) is selected from the group consisting of

wherein, * represents the point of attachment to Q;

-   D³ is independently selected from the group consisting of    —C(R⁵⁵)(R⁶⁶)—, —C(R⁵⁵)(OH)—, —C(O)—, —O—, —N(R⁷⁷)— and —S(O)₀₋₂—;

-   are independently selected from the group consisting of phenyl,    heteroaryl and heterocyclyl, wherein each phenyl, heteroaryl and    heterocyclyl is optionally substituted with one to three    substituents independently selected from the group consisting of    halo, —CF₃, —OCF₃, —NO₂, —CN, —C₁-C₆alkyl, —C₁-C₆alkoxyl,    —O—C₂-C₆alkyl-O—R⁵³, —O—R⁵³, —C₀-C₆alkyl-S(O)₀₋₂—R⁵³,    —C₀-C₆alkyl-C(O)—R⁵³, —C₀-C₆alkyl-C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-NR⁵²C(O)—R⁵³, —C₀-C₆alkyl-S(O)₂NR⁵⁰R⁵¹,    —C₀-C₆alkyl-NR⁵²S(O)₂—R⁵³, —C₀-C₆alkyl-OC(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-NR⁵²C(O)O—R⁵³, —C₀-C₆alkyl-NR⁵²C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-C(O)O—R⁵³, —C₀-C₆alkyl-OC(O)—R⁵³, —C₀-C₆alkyl-aryl,    —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-C₃-C₇cycloalkyl,    —C₀-C₆alkyl-heterocyclyl, —C₀-C₆alkyl-NR⁵⁰R⁵¹,    —O—C₂-C₆alkyl-NR⁵⁰R⁵¹, —NR⁵³—C₂-C₆alkyl-NR⁵⁰R⁵¹ and    —O-heterocyclyl-R⁵³;-   R⁴⁴ is independently selected from the group consisting of —H,    —C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₇cycloalkyl and    —C₀-C₄alkyl-heterocyclyl;-   R⁵⁰ and R⁵¹ are independently selected from the group consisting of    H, —C₁-C₆alkyl, —C₂-C₆alkyl-O—C₁-C₆alkyl,    —C₀-C₆alkyl-C₃-C₇cycloalkyl, wherein each alkyl and cycloalkyl is    optionally substituted with one or more substituents independently    selected from the group consisting of halo, —OH, amino, —CN or    —C₁-C₄alkyl;    or-   R⁵⁰ and R⁵¹, together with the N atom to which they are attached,    optionally form a 3-10 membered heterocyclic ring, wherein the    heterocyclyl is optionally substituted with one to three    substituents independently selected from the group consisting of    halo, —OH, amino, —CN or —C₁-C₄alkyl;-   R⁵² is independently selected atom the group consisting of —H,    —C₁-C₆alkyl, —C₂-C₆alkyl-O—C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₇cycloalkyl,    wherein each alkyl and cycloalkyl is optionally substituted with one    or more substituents independently selected from the group    consisting of halo, —OH, amino, —CN or —C₁-C₄alkyl;-   R⁵³ is independently selected from the group consisting of    —C₁-C₆alkyl, —C₀-C₄alkyl-C₃-C₇cycloalkyl, —C₀-C₄alkyl-aryl,    —C₀-C₄alkyl-heteroaryl and —C₀-C₄alkyl-heterocyclyl, wherein each    alkyl, aryl, heteroaryl and heterocyclyl is optionally substituted    with one or three substituents independently selected from the group    consisting of halo, —OH, amino, —CN or —C₁-C₄alkyl;-   R⁵⁵ and R⁶⁶ are independently selected from the group consisting of    —H, —C₁-C₆alkyl, —C₁-C₆alkoxyl, —C₀-C₄alkyl-C₃-C₇cycloalkyl and    —C₀-C₄alkyl-heterocyclyl;    or-   R⁵⁵ and R⁶⁶, together with the atom to which they are attached,    optionally form a 3-7 membered cycloalkyl or heterocyclic ring,    wherein each cycloalkyl and heterocyclyl is optionally substituted    with one to three substituents independently selected from the group    consisting of halo, —OH, amino, —CN or —C₁-C₄alkyl;-   R⁷⁷ is independently selected from the group consisting of —H,    —C₁-C₆alkyl, —C₁-C₆heteroalkyl, —C₃-C₇cycloalkyl, —C(O)—R⁵³,    —C(O)O—R⁵³, -cycloalkyl, —C₁-C₄alkyl-cycloalkyl, phenyl,    —C₁-C₄alkyl-phenyl, -heterocyclyl, —C₁-C₄alkyl-heterocyclyl and    —C₂-C₆alkyl-NR⁸⁸R⁹⁹, wherein each alkyl and heteroalkyl is    optionally substituted with one or three substituents independently    selected from the group consisting of F, —OH and oxo, wherein each    phenyl, cycloalkyl and heterocyclyl is optionally substituted with    one or two substituents independently selected from the group    consisting of halo, —CN, —C₁-C₄alkyl, —C₁-C₄alkoxyl,    —O—C₂-C₄alkyl-O—C₁-C₄alkyl, —CF₃, —OCF₃, —NO₂,    —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ and    —N(C₁-C₆alkyl)₂;-   or R⁷⁷ together with the N to which it is attached may form a ring    with

wherein the ring is a 5-7 membered heterocyclic ring, and

-   R⁸⁸ and R⁹⁹ are independently selected from the group consisting of    —H, —C₁-C₆alkyl, —C₂-C₆alkyl-O—C₁-C₆alkyl and    —C₀-C₄alkyl-C₃-C₇cycloalkyl, wherein each cycloalkyl and alkyl is    optionally substituted with one to three substituents independently    selected from the group consisting of halo, —OH, amino, —CN or    —C₁-C₆alkyl-aryl;    or-   R⁸⁸ and R⁹⁹, together with the N atom to which they are attached,    optionally form a 3-10 membered heterocyclic ring, wherein an    heterocyclyl is optionally substituted with one to three    substituents independently selected from the group consisting of    halo, —OH, amino or —CN

In a preferred embodiment of embodiment VV, embodiment VV-1, of thecompounds of the present invention,

-   J-Q is selected from the group consisting of —C₁-C₉alkyl,    —C₁-C₉heteroalkyl, phenyl, aryl, heteroaryl, —C₁-C₄alkyl-phenyl,    —C₁-C₄alkyl-aryl, —C₁-C₄alkyl-heteroaryl, —NR³³aryl,    —NR³³—C₁-C₄alkyl-aryl, —NR³³heteroaryl and    NR³³—C₁-C₄alkyl-heteroaryl, wherein each alkyl and heteroalkyl is    optionally substituted with one or three substituents independently    selected from the group consisting of F, —OH and oxo, wherein each    phenyl, aryl and heteroaryl is optionally substituted with one or    two substituents independently selected from the group consisting of    halo, —OH, —OR⁵³, —C₁-C₄alkyl, —C₁-C₄alkoxyl,    —O—C₂-C₄alkyl-O—C₁-C₆alkyl, —CN, —CF₃, —OCF₃, —NO₂,    —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ and    —N(C₁-C₆alkyl)₂, wherein R³³ is independently selected from the    group consisting of —H, —C₁-C₆alkyl, —C₀-C₆alkyl-C₃-C₇cycloalkyl and    —C₀-C₄alkyl-phenyl, wherein each phenyl and cycloalkyl is optionally    substituted with one or three substituents independently selected    from the group consisting of halo, —OH, —NO₂, —CF₃, —OCF₃, amino,    —N(C₁-C₆alkyl)₂, —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —C₁-C₄alkoxyl-CN,    —O—C₂alkyl-O—CH₃, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ or —C₁-C₄alkyl.

In a preferred embodiment of embodiment VV, embodiment VV-2, of thecompounds of the present invention, the moiety

In a preferred embodiment of embodiment VV, embodiment VV-3, of thecompounds of the present invention,

J-Q is selected from the group consisting of 5- or 6-memberedheteroaryl.

In a preferred embodiment of embodiment VV, embodiment VV-4, of thecompounds of the present invention, the compounds are represented by theFormula (III):

wherein R¹⁴⁰ is selected from the group consisting of H, —OH, halo, —CN,—C₁-C₄alkyl, —C₁-C₄alkoxyl, —O—C₂-C₄alkyl-O—C₁-C₄alkyl, —CF₃, —OCF₃,—NO₂, —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ and—N(C₁-C₆alkyl)₂.

In a preferred embodiment of embodiment VV-4, embodiment VV-5, of thecompounds of the present invention,

D^(1a)-D^(2a) is selected from the group consisting of

In a preferred embodiment of embodiment VV-4, embodiment VV-6, of thecompounds of the present invention,

D^(1a)-D^(2a) is

In a preferred embodiment of embodiment VV-4, embodiment VV-7, of thecompounds of the present invention,

D^(1a)-D^(2a) is

andD³ is selected from the group consisting of —C(R⁵⁵)(R⁶⁶)—, —C(R⁵⁵)(OH)—,—C(O)—, —O—, —N(R⁷⁷)— and —S(O)₀₋₂.

In a preferred embodiment of embodiment VV-4, embodiment VV-8, of thecompounds of the present invention,

D^(1a)-D^(2a) is

and

D³ is —N(R⁷⁷)—.

In a preferred embodiment of embodiment VV-4, embodiment VV-9, of thecompounds of the present invention,

D^(1a)-D^(2a) is

and

D³ is —O—.

In a preferred embodiment of embodiment VV-4, embodiment VV-10, of thecompounds of the present invention,

D^(1a)-D^(2a) is

D³ is —O—; and

are independently selected from the group consisting of phenyl, pyridyl,pyrimidyl, thienyl, pyrazolyl, thiazyl and oxazyl.

In a preferred embodiment of embodiment VV-4, embodiment VV-11, of thecompounds of the present invention,

D^(1a)-D^(2a) is

D³ is —O—; and

are independently selected from the group consisting of phenyl, pyridyl,pyrimidyl, thienyl, pyrazolyl, thiazyl and oxazyl, wherein at least oneof

is phenyl, wherein the phenyl, pyridyl, pyrimidyl, thienyl, pyrazolyl,thiazyl and oxazyl are independently optionally substituted.

In a preferred embodiment of embodiment VV-4, embodiment VV-12, of thecompounds of the present invention,

D^(1a)-D^(2a) is

D³ is —N(R⁷⁷)—.

are independently selected from the group consisting of phenyl, pyridyl,pyrimidyl and thienyl.

In a preferred embodiment of embodiment VV-4, embodiment VV-13, of thecompounds of the present invention,

D^(1a)-D^(2a) is

D³ is —N(R⁷⁷)—; and

are independently selected from the group consisting of phenyl, pyridyl,pyrimidyl and thienyl, wherein at least one of

is phenyl, wherein said phenyl, pyridyl, pyrimidyl and thienyl areindependently optionally substituted.

In a preferred embodiment of embodiment VV, embodiment VV-14, of thecompounds of the present invention, the compounds are represented by theFormula (IV):

wherein R¹⁴⁰, is as defined in Formula III;

-   xa and xb denote numbers that are each independently selected from    0, 1 and 2; and-   R¹⁵⁰ and R¹⁶⁰ are independently selected from the group consisting    of H, halo, —CN, —CF₃, —OCF₃, —C₁-C₆alkyl, —C₁-C₆alkoxyl,    —O—C₂-C₆alkyl-O—R⁵³, —OR⁵³, —C₀-C₆alkyl-S(O)₀₋₂—R⁵³,    —C₀-C₆alkyl-C(O)—R⁵³, —C₀-C₆alkyl-C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-NR⁵²C(O)—R⁵³, —C₀-C₆alkyl-S(O)₂NR⁵⁰R⁵¹,    —C₀-C₆alkyl-NR⁵²S(O)₂—R⁵³, —C₀-C₆alkyl-OC(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-NR⁵²C(O)O—R⁵³, —C₀-C₆alkyl-NR⁵²C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-C(O)O—R⁵³, —C₀-C₆alkyl-OC(O)—R⁵³, —C₀-C₆alkyl-aryl,    —C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-cycloalkyl,    —C₀-C₆alkyl-heterocyclyl, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹,    —O—C₂-C₆alkyl-NR⁵⁰R⁵¹, —NR⁵³—C₂-C₆alkyl-NR⁵⁰R⁵¹ and    —O-heterocyclyl-R⁵³, wherein each alkyl and heteroalkyl is    optionally substituted with one or three substituents independently    selected from the group consisting of F, —OH and oxo, and wherein    each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally    substituted with one or two substituents independently selected from    the group consisting of halo, —CN, —C₁-C₄alkyl, —C₁-C₄alkoxyl,    —O—C₂-C₄alkyl-O—C₁-C₄alkyl, —CF₃, —OCF₃, —NO₂,    —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ and    —N(C₁-C₆alkyl)₂;

In a preferred embodiment of embodiment VV, embodiment VV-15, of thecompounds of the present invention, the compounds are represented by theFormula (V):

wherein R¹⁴⁰ is as defined in Formula III, and xb, R¹⁵⁰ and R¹⁶⁰ are asdefined in Formula IV;

-   xc is 0 or 1; and-   R¹⁷⁰ is selected from the group consisting of H, halo, —CN, —CF₃,    —OCF₃, —C₁-C₆alkyl, —C₁-C₆alkoxyl, —O—C₂-C₆alkyl-O—R⁵³, —OR⁵³,    —C₀-C₆alkyl-S(O)₀₋₂—R⁵³, —C₀-C₆alkyl-C(O)—R⁵³,    —C₀-C₆alkyl-C(O)NR⁵⁰R⁵¹, —C₀-C₆alkyl-NR⁵²C(O)—R⁵³,    —C₀-C₆alkyl-S(O)₂NR⁵⁰R⁵¹, —C₀-C₆alkyl-NR⁵²S(O)₂—R⁵³,    —C₀-C₆alkyl-OC(O)NR⁵⁰R⁵¹, —C₀-C₆alkyl-NR⁵²C(O)O—R⁵³,    —C₀-C₆alkyl-NR⁵²C(O)NR⁵⁰R⁵¹, —C₀-C₆alkyl-C(O)O—R⁵³,    —C₀-C₆alkyl-OC(O)—R⁵³, —C₀-C₆alkyl-aryl, —C₀-C₆alkyl-heteroaryl,    —C₀-C₆alkyl-cycloalkyl, —C₀-C₆alkyl-heterocyclyl, —NH₂, —NR⁵⁰R⁵¹,    —C₁-C₆alkyl-NR⁵⁰R⁵¹, —O—C₂-C₆alkyl-NR⁵⁰R⁵¹, —NR⁵³—C₂-C₆alkyl-NR⁵⁰R⁵¹    and —O-heterocyclyl-R⁵³, wherein each alkyl and heteroalkyl is    optionally substituted with one or three substituents independently    selected from the group consisting of F, —OH and oxo, wherein each    aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally    substituted with one or two substituents independently selected from    the group consisting of halo, —CN, —C₁-C₄alkyl, —C₁-C₄alkoxyl,    —O—C₂-C₄alkyl-O—C₁-C₄alkyl, —CF₃, —OCF₃, —NO₂,    —C₁-C₆alkyl-S(O)₀₋₂R⁵³, —NH₂, —NR⁵⁰R⁵¹, —C₁-C₆alkyl-NR⁵⁰R⁵¹ and    —N(C₁-C₆alkyl)₂.

In a preferred embodiment of embodiment VV, embodiment VV-16, of thecompounds of the present invention, the compounds represented by theFormula (VI):

wherein R¹⁷⁰ is as defined in Formula V.

In a preferred embodiment of embodiment VV, embodiment VV-17, of thecompounds of the present invention, the compounds are represented by theFormula (VII):

wherein R¹⁴⁰ is as defined in Formula III, xa, xb, R¹⁵⁰ and R¹⁶⁰ are asdefined in Formula IV; and R³ is as defined in Formula I.

In a preferred embodiment of embodiment VV, embodiment VV-18, of thecompounds of the present invention, R³ is R¹⁸⁰, wherein

-   R¹⁸⁰ is selected from the group consisting of H, —C₁-C₆alkyl,    —C₁-C₆alkenyl, —C₁-C₆alkynyl, —C₂-C₆alkoxyl, —C₂-C₆alkyl-O—R⁵³,    —OR⁵³, —C₂-C₆alkyl-S(O)₀₋₂—R⁵³, —C₂-C₆alkyl-C(O)—R⁵³,    —C₂-C₆alkyl-C(O)NR⁵⁰R⁵¹, —C₂-C₆alkyl-NR⁵²C(O)—R⁵³,    —C₂-C₆alkyl-S(O)₂NR⁵⁰R⁵¹, —C₂-C₆alkyl-NR⁵²S(O)₂—R⁵³,    —C₂-C₆alkyl-OC(O)NR⁵²C(O)—R⁵³, —C₂-C₆alkyl-NR⁵²C(O)O—R⁵³,    —C₂-C₆alkyl-NR⁵²C(O)NR⁵⁰R⁵¹, —C₂-C₆alkyl-C(O)O—R⁵³,    —C₂-C₆alkyl-OC(O)—R⁵³, —C₁-C₆alkyl-heterocyclyl-R⁵³,    —C₀-C₆alkyl-heterocyclyl-O—R⁵³,    —C₀-C₆alkyl-heterocyclyl-S(O)₀₋₂—R⁵³,    —C₀-C₆alkyl-heterocyclyl-C(O)—R⁵³,    —C₀-C₆alkyl-heterocyclyl-C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-heterocyclyl-NR⁵²C(O)—R⁵³,    —C₀-C₆alkyl-heterocyclyl-S(O)₂NR⁵⁰R⁵¹,    —C₀-C₆alkyl-heterocyclyl-NR⁵²S(O)₂—R⁵³,    —C₀-C₆alkyl-heterocyclyl-OC(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-heterocyclyl-NR⁵²C(O)O—R⁵³,    —C₀-C₆alkyl-heterocyclyl-NR⁵²C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-heterocyclyl-C(O)O—R⁵³,    —C₀-C₆alkyl-heterocyclyl-OC(O)—R⁵³, —C₁-C₆alkyl-cycloalkyl-R⁵³,    —C₀-C₆alkyl-cycloalkyl —O—R⁵³, —C₀-C₆alkyl-cycloalkyl —S(O)₀₋₂—R⁵³,    —C₀-C₆alkyl-cycloalkyl-C(O)—R⁵³, —C₀-C₆alkyl-cycloalkyl    —C(O)NR⁵⁰R⁵¹, —C₀-C₆alkyl-cycloalkyl-NR⁵²C(O)—R⁵³,    —C₀-C₆alkyl-cycloalkyl-S(O)₂NR⁵⁰R⁵¹,    —C₀-C₆alkyl-cycloalkyl-NR⁵²S(O)₂—R⁵³,    —C₀-C₆alkyl-cycloalkyl-OC(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-cycloalkyl-NR⁵²C(O)O—R⁵³,    —C₀-C₆alkyl-cycloalkyl-NR⁵²C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-cycloalkyl-C(O)O—R⁵³, —C₀-C₆alkyl-cycloalkyl-OC(O)—R⁵³,    —C₀-C₆alkyl-heteroaryl-R⁵³, —C₀-C₆alkyl-heteroaryl —O—R⁵³,    —C₀-C₆alkyl-heteroaryl —S(O)₀₋₂—R⁵³, —C₀-C₆alkyl-heteroaryl    —C(O)—R⁵³, —C₀-C₆alkyl-heteroaryl —C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-heteroaryl —NR⁵²C(O)—R⁵³, —C₀-C₆alkyl-heteroaryl    —S(O)₂NR⁵⁰R⁵¹, —C₀-C₆alkyl-heteroaryl —NR⁵²S(O)₂—R⁵³,    —C₀-C₆alkyl-heteroaryl —OC(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-heteroaryl-NR⁵²C(O)O—R⁵³, —C₀-C₆alkyl-heteroaryl    —NR⁵²C(O)NR⁵⁰R⁵¹, —C₀-C₆alkyl-heteroaryl —C(O)O—R⁵³,    —C₀-C₆alkyl-heteroaryl —OC(O)—R⁵³, —C₀-C₆alkyl-aryl-R⁵³,    —C₀-C₆alkyl-aryl —O—R⁵³, —C₁-C₆alkyl-aryl —S(O)₀₋₂—R⁵³,    —C₀-C₆alkyl-aryl —C(O)—R⁵³, —C₀-C₆alkyl-aryl —C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-aryl —NR⁵²C(O)—R⁵³, —C₀-C₆alkyl-aryl —S(O)₂NR⁵⁰R⁵¹,    —C₀-C₆alkyl-aryl —NR⁵²S(O)₂—R⁵³, —C₀-C₆alkyl-aryl —OC(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-aryl-NR⁵²C(O)O—R⁵³, —C₀-C₆alkyl-aryl —NR⁵²C(O)NR⁵⁰R⁵¹,    —C₀-C₆alkyl-aryl —C(O)O—R⁵³, —C₀-C₆alkyl-aryl —OC(O)—R⁵³,    —C₀-C₆alkyl-aryl, —C₁-C₆alkyl-heteroaryl, —C₀-C₆alkyl-cycloalkyl,    —C₀-C₆alkyl-heterocyclyl and —C₂-C₆alkyl-NR⁵⁰R⁵¹, wherein each alkyl    and heteroalkyl is optionally substituted with one to three    substituents independently selected from the group consisting of F,    —OH and oxo, wherein each aryl, heteroaryl, cycloalkyl and    heterocyclyl is optionally substituted with one or two substituents.

In a preferred embodiment of embodiment VV, embodiment VV-19, thecompound is selected from the group consisting of:

-   (Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(dibenzo[b,f][1,4]thiazepin-11-yl)-N-hydroxybenzamide,-   4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   N-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(benzo[b]pyrido[3,2-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide,-   (Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(2-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(benzo[b]pyrido[4,3-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide,-   (Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-2-fluoro-N-hydroxybenzamide,-   (Z)-5-(4-(hydroxycarbamoyl)phenyl)benzo[b]pyrido[4,3-f][1,4]oxazepine    2-oxide,-   (Z)-N-hydroxy-4-(3-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-3-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(8-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(9-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(7-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(8-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(4-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(3-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(benzo[b]thieno[2,3-f][1,4]oxazepin-10-yl)-N-hydroxybenzamide,-   (Z)-4-(3-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(6-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(7-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(4-hydroxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(1-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(4-(2-methoxyethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(1-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)benzamide,-   (Z)-4-(11-cyclopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide,-   (Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(4-(2-morpholinoethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)-N-hydroxybenzamide,-   (Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(4-(methylthio)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(4-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-4-(5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(4-(methylsulfonyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (E)-4-((dibenzo[b,f][1,4]oxazepin-11-ylamino)methyl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(4-methoxy-8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(3-morpholinodibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(4-propyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(4-(trifluoromethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (Z)-N-hydroxy-4-(6-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,-   (E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N-hydroxybenzamide,-   (E)-6-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxynicotinamide,-   (E)-5-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxyfuran-2-carboxamide,-   (E)-5-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxythiophene-2-carboxamide,-   (Z)-4-(5-ethyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,-   (Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxy-N-methylbenzamide,-   (Z)-N-hydroxy-4-(5-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzamide,-   (E)-4-((5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamino)methyl)-N-hydroxybenzamide,-   (Z)-4-(4-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(5-(2-methoxyethyl)-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzamide,-   (E)-4-(2-(dibenzo[b,f][1,4]oxazepin-11-ylamino)ethyl)-N-hydroxybenzamide,-   (Z)-4-(11-ethyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide,-   (Z)-4-(5-cyclopropyl-2-fluoro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(11-isopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide,-   (Z)-4-(benzo[f]thieno[2,3-b][1,4]oxazepin-5-yl)-N-hydroxybenzamide,-   (Z)-6-(4-(dibenzo[b,f][1,4]oxazepin-11-yl)benzamidooxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic    acid,-   (Z)-N-hydroxy-4-(11-(3-morpholinopropyl)-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide,-   (Z)-N-hydroxy-4-(11-(2-morpholinoethyl)-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide,-   (Z)-4-(11-(cyclopropylmethyl)-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide,-   (Z)-N-hydroxy-4-(5-(2-morpholinoethyl)-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzamide,

In a preferred embodiment, embodiment WW, of the compounds according tothe present invention, the compounds are represented by the FormulaVIII:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs, polymorphs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof, whereinwherein R⁴ and A are as defined in Formula I;

Z is —N(R¹)OR² or H;

L is a covalent bond or —C₀-C₃alkyl-N(OR²)—;wherein, when L is C₀-C₃alkyl-N(OR²)—, then Z is H; andwherein, when Z is H, then L is —C₀-C₃alkyl-N(OR²)—;G2 is carbon or N;U² is selected from the group consisting of a covalent bond,—C₁-C₈alkyl-, —C(R³⁰⁰)(R⁴⁰⁰)—, —C(O)—C(R³⁰¹)(R⁴⁰¹)—,—C₀-C₂alkyl-C(O)—O—C₀-C₄alkyl-, —C₀-C₂alkyl-C(O)—C₀-C₄alkyl-,—C₀-C₂alkyl-C(O)—NR³—C₀-C₄alkyl-, —C(O)—O—C(R³⁰¹)(R⁴⁰¹),—C(O)—C(R³⁰¹)(R⁴⁰¹) and —C(O)—NR³—C(R³⁰⁰)(R⁴⁰⁰)—,wherein R³ and R^(3a) are as defined in Formula I;R³⁰⁰ and R⁴⁰⁰ are independently selected from the group consisting of—H, —F, —C₁-C₆alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl;R³⁰¹ and R⁴⁰¹ are independently selected from the group consisting of—H, F, OR¹, —NR³R^(3a)—, —C₁-C₆alkyl, aryl, heteroaryl, heterocyclyl andcycloalkyl;R²⁰⁰, R²⁰¹, R²⁰² and R²⁰³ are independently selected from the groupconsisting of —H, —C₁-C₆alkyl, aryl, heteroaryl, heterocyclyl andcycloalkyl; and

is selected from the group consisting of hydrogen, aryl, heteroaryl,alkyl, heterocyclyl, cycloalkyl, wherein each aryl, heteroaryl,cycloalkyl and heterocyclyl is optionally substituted with one to threesubstituents independently selected from the group consisting of halo,—CF₃, —OCF₃, —SCF₃, —SF₅, —NO₂, —CN, —C₁-C₆alkyl, —C₁-C₆alkoxyl,—O—C₂-C₆alkyl-O—R¹, —O—R¹, —OCF₂H, —C₀-C₆alkyl-S(O)₀₋₂—R¹,—C₀-C₆alkyl-C(O)—R¹, —C₀-C₆alkyl-C(O)NR³R^(3a), —C₀-C₆alkyl-NR³C(O)—R²,—C₀-C₆alkyl-S(O)₂NR³R^(3a), —C₀-C₆alkyl-NR³S(O)₂—R²,—C₀-C₆alkyl-OC(O)NR³R^(3a), —C₀-C₆alkyl-NR³C(O)O—R¹,—C₀-C₆alkyl-NR¹C(O)NR³R^(3a), —C₀-C₆alkyl-C(O)O—R¹,—C₀-C₆alkyl-OC(O)—R¹, —C₀-C₆alkyl-aryl, —C₀-C₆alkyl-heteroaryl,—C₀-C₆alkyl-C₃-C₇cycloalkyl, —C₀-C₆alkyl-heterocyclyl,—C₀-C₆alkyl-NR³R^(3a) and —O—C₂-C₆alkyl-NR³R^(3a);

In a preferred embodiment of embodiment WW, embodiment WW-1, the moiety

In a preferred embodiment of embodiment WW, embodiment WW-2, the moiety

In a preferred embodiment of embodiment WW, embodiment WW-3, the moiety

is a radical selected from the group consisting of

In a preferred embodiment of embodiment WW, embodiment WW-4, the moiety

is a radical

or an enantiomer thereof, a scalemic thereof, or a mixture ofenantiomers thereof.

In a preferred embodiment of embodiment WW, embodiment WW-5, U² is acovalent bond.

In a preferred embodiment of embodiment WW, embodiment WW-6, U² isselected from the group consisting of a —C₁-C₄alkyl, —CH(aryl)-,—CH(heteroaryl)-, —C(O)—, —C(O)—CH(aryl)-, —C(O)—CH(heteroaryl)-,—C(O)O—C₁-C₂alkyl-, —C(O)O— and —C(O)NH—.

In a preferred embodiment of embodiment WW, embodiment WW-7, the moiety

is a radical selected from the group consisting of H, alkyl, aryl,heteroaryl, cycloalkyl and heterocyclyl, wherein each aryl, heteroaryl,cycloalkyl and heterocyclyl is optionally substituted with one to threesubstituents independently selected from the group consisting of halo,—CF₃, —OCF₃, —SCF₃, —SF₅, —CN, —C₁-C₆alkyl, —O—C₂-C₆alkyl-O—R¹, —O—R¹,—OCF₂H, —C₀-C₆alkyl-S(O)₀₋₂—R¹, —C₀-C₆alkyl-C(O)NR³R^(3a),—C₀-C₆alkyl-NR³C(O)—R², —C₀-C₆alkyl-S(O)₂NR³R^(3a),—C₀-C₆alkyl-NR³S(O)₂—R², —C₀-C₆alkyl-OC(O)NR³R^(3a),—C₀-C₆alkyl-NR³C(O)O—R¹, —C₀-C₆alkyl-NR¹C(O)NR³R^(3a),—C₀-C₆alkyl-C(O)O—R¹, —C₀-C₆alkyl-OC(O)—R¹, —C₀-C₆alkyl-aryl,—C₀-C₆alkyl-heteroaryl, —C₀-C₆alkyl-C₃-C₇cycloalkyl,—C₀-C₆alkyl-heterocyclyl, —C₀-C₆alkyl-NR³R^(3a) and—O—C₂-C₆alkyl-NR³R^(3a).

In a preferred embodiment of embodiment WW, embodiment WW-8, the moiety

is a radical selected from the group consisting of

In a preferred embodiment of embodiment WW, embodiment WW-9, thecompounds are represented by the Formula (IX):

or where possible, a (R,R) or (S,S) enantiomer, scalemic or a mixture ofenantiomers thereof,wherein

and U₂ are as defined in Formula (VIII); andA, R¹, R² and R⁴ are as defined in Formula I.

In a preferred embodiment of embodiment WW, embodiment WW-10, thecompounds are represented by the Formula (X):

or where possible, a (R,R) or (S,S) enantiomer, scalemic or a mixture ofenantiomers thereof,wherein

is as defined in Formula (VIII); andA and R⁴ are as defined in Formula I.

In a preferred embodiment of embodiment WW, embodiment WW-11, the moiety

is a radical selected from the group consisting of

In a preferred embodiment of embodiment WW, embodiment WW-12, thecompound is selected from the group consisting of:

-   2-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-benzhydryl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   (1S,4S)-tert-butyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   2-((1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-o-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-phenyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-benzoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(2-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(4-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)benzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-(benzo[d][1,3]dioxol-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(cyclohexanecarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(2,2-diphenylacetyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-4-((1S,4S)-5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   (1S,4S)-benzyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   (1S,4S)-isobutyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethoxy)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethylthio)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(2-(trifluoromethyl)quinolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-((1S,4S)-5-(3-(difluoromethoxy)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(6-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   (1S,4S)-cyclopentyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   2-((1S,4S)-5-(benzo[c][1,2,5]oxadiazol-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(5-(trifluoromethyl)pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1R,4R)-5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   (1S,4S)-isopropyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   (1S,4S)-pyridin-3-ylmethyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   (1S,4S)-cyclopropylmethyl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   (1S,4S)-tetrahydro-2H-pyran-4-yl    5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate,-   2-((1S,4S)-5-(3,5-bis(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(benzo[d]isoxazol-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(3-(dimethylcarbamoyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   2-((1S,4S)-5-(3-((dimethylamino)methyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-6-(5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)nicotinamide,-   N-hydroxy-5-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrazine-2-carboxamide,-   2-fluoro-N-hydroxy-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-2-((1S,4S)-5-(pyrrolidine-1-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1S,4S)-5-(4-(trifluoromethyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-6-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridazine-3-carboxamide,-   N-hydroxy-2-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   N-hydroxy-2-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide,-   2-(5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide,-   N-hydroxy-4-(5-(3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-4-(5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-4-((1S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   4-((1S,4S)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxybenzamide,-   N-hydroxy-4-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-4-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-4-((1S,4S)-5-(4-(trifluoromethyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide,-   N-hydroxy-N-methyl-4-((1S,4S)-5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide    and

In a preferred embodiment of the compounds according to the presentinvention, embodiment XX, the compounds are represented by the Formula(XI):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs, polymorphs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof,wherein

Q¹ is selected from the group consisting of —C₁-C₆alkyl, covalent bond,—C₀-C₆alkyl-O—C₀-C₆alkyl-, —C₀-C₆alkyl-NR³—C₀-C₆alkyl-,—C₀-C₆alkyl-S(O)₀₋₂—C₀-C₆alkyl-, —C₀-C₆alkyl-NR³C(O)—C₀-C₆alkyl-,—C₀-C₆alkyl-C(O)NR³—C₀-C₆alkyl- and —C₀-C₆alkyl-OC(O)NR³—C₀-C₆alkyl-;andR¹, R⁴, M¹-M², M³, A, D¹-D₂, D³ are as defined in Formula I.

In a preferred embodiment of embodiment XX, embodiment XX-1, the moiety

is selected from a radical consisting of

wherein R⁴ is as defined in Formula I.

In a preferred embodiment, embodiment YY, of the compounds according tothe present invention, the compounds are represented by the Formula(XII):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs, polymorphs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof,

whereinQ² is selected from the group consisting of —C₁-C₆alkyl, covalent bond,—C₀-C₆alkyl-O—C₀-C₆alkyl-, —C₀-C₆alkyl-NR₃—C₀-C₆alkyl-,—C₀-C₆alkyl-S(O)₀₋₂—C₀-C₆alkyl-, —C₀-C₆alkyl-NR₃C(O)—C₀-C₆alkyl-,—C₀-C₆alkyl-C(O)NR₃—C₀-C₆alkyl- and —C₀-C₆alkyl-OC(O)NR₃—C₀-C₆alkyl-;andR³, R⁴, M¹-M², M³, A, D-D², D³ are as defined in Formula I;

In a preferred embodiment of embodiment YY, embodiment YY-1, the moiety

is selected from a radical consisting of

wherein R⁴ is as defined in Formula I.

In a preferred embodiment, embodiment ZZ, of the compounds according tothe present invention, the compounds are represented by the Formula(XIII):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs, polymorphs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof,wherein

is a radical selected from the group consisting of

R⁴, M¹-M², M³, A, D¹-D², D³ are as defined in Formula I.

In a preferred embodiment, embodiment AAA, of the compounds according tothe present invention, the compounds are represent by the Formula (XIV):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs, polymorphs and complexes thereof, and racemic and scalemicmixtures, diastereomers and enantiomers thereof,

whereinis a radical selected from the group consisting of aryl, heteroaryl,heterocyclyl, cycloalkyl,

wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionallysubstituted; and wherein Q, R⁴, M¹-M², M³, A, D¹-D², D³ are as definedin Formula I.

Some examples of the compounds according to the first aspect of theinvention are given below. These examples merely serve to exemplify someof the compounds of the first aspect of the invention and do not limitthe scope of the invention:

SYNTHETIC SCHEMES AND EXPERIMENTAL PROCEDURES

The compounds of the invention can be prepared according to the reactionschemes for the examples illustrated below utilizing methods known toone of ordinary skill in the art. These schemes serve to exemplify someprocedures that can be used to make the compounds of the invention. Oneskilled in the art will recognize that other general syntheticprocedures may be used. The compounds of the invention can be preparedfrom starting components that are commercially available. Any kind ofsubstitutions can be made to the starting components to obtain thecompounds of the invention according to procedures that are well knownto those skilled in the art.

Example 1 (Z)-4-(Dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (3)Step 1: (E)-11-Chlorodibenzo[b,f][1,4]oxazepine (1)

A solution of 10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one (1.00 g, 4.74mmol) and phosphorus oxychloride (40 mL) was stirred for 5 h at reflux.The reaction mixture was then cooled to room temperature andconcentrated under reduced pressure. The residue was dissolved intoAcOEt and washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated to give an orange oil. The residuewas purified by silica gel column chromatography with EtOAc (10%) inHexanes to afford 1 (939 mg, 86%) as a yellow solid. LRMS (ESI): (calc)229.0 (found) 230.1 (MH)⁺.

Step 2: (Z)-Methyl 4-(dibenzo[b,f][1,4]oxazepin-11-yl)benzoate (2)

To a solution of 1 (229 mg, 1.00 mmol) in DME (3 mL) was added4-methoxycarbonylphenylboronic acid (216 mg, 1.20 mmol), Pd(PPh₃)₄(0.065 mg, 0.056 mmol) and 2 N Na₂CO_(3(aq)) (1.5 mL, 3.0 mmol). Thereaction mixture was stirred for 2 h at 90° C. The solution was thencooled at room temperature and poured into AcOEt. The organic layer waswashed with water, brine and dried (Na₂SO₄), filtered and concentratedto give a yellow oil. The residue was purified by silica gel columnchromatography with EtOAc (15%) in Hexanes to afford 2 (327 mg, 99%) asa yellow foam. LRMS (ESI): (calc) 329.1 (found) 330.3 (MH)⁺.

Step 3: (Z)-4-(Ddibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (3)

To a stirring solution of ester 2 (327 mg, 1.00 mmol) in MeOH (4.0 mL)and THF (4.0 mL) was added hydroxylamine (1.2 mL, excess, 50% in water)followed by KOH (212 mg, 4.00 mmol) and the reaction mixture was stirredat room temperature for 15 min. The reaction mixture was concentratedunder vacuum. 3N HCl was added to the residue to reach pH=7-8. Themixture was extracted with ethyl acetate (3×). The combined organicphases were washed with water (2×) and brine, dried over sodium sulfateand concentrate in vacuo to one third volume. Hexane was added to themixture and the solid was filtered. The crude product was purified byflash eluting with 75% ethyl acetate in hexanes to afford the titlecompound (3) as a yellow solid (35 mg, 11%). ¹H NMR (DMSO-d₆) δ (ppm):11.37 (br s, 1H), 9.14 (br s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.81 (d,J=8.8 Hz, 2H), 7.66-7.62 (m, 1H), 7.43-7.39 (m, 2H), 7.32-7.25 (m, 4H),7.17 (dd, J=8.0, 1.6 Hz, 1H). LRMS (ESI): (calc) 330.1 (found) 331.4(MH)⁺.

Example 24-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (6)Step 1: (Z)-ethyl 4-(dibenzo[b,f][1,4]oxazepin-11-yl)benzoate (4)

Using Procedure B (Table 1) with compound 1 and4-(ethoxycarbonyl)phenylboronic acid the title compound 4 was obtained(2.76 g, 83%) as a yellow foam. LRMS (ESI): (calc) 343.12 (found) 344.3(MH)⁺.

Step 2: ethyl 4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzoate(5)

Title compound 4 was dissolved in ethanol (25 mL) and THF (5 mL).Platinum (IV) oxide (0.075 g, 10% wt) was added. The mixture was stirredat room temperature for 3 h under 1 atmosphere of hydrogen. The catalystwas filtered and the filtrate was concentrated under reduced pressure toone third volume. The precipitate was filtered to afford title compound5 (510 mg, 67%) as a white solid. LRMS (ESI): (calc) 345.14 (found)346.3 (MH)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.88 (d, J=8.4 Hz, 2H),7.48 (dd, J=7.5, 1.7 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.33 (td, J=7.7,1.8 Hz, 1H), 7.19 (td, J=7.4, 1.2 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H),6.90-6.83 (m, 3H), 6.77 (dd, J=7.9, 1.4 Hz, 1H), 6.50 (td, J=7.3, 1.6Hz, 1H), 5.55 (d, J=6.1 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 1.28 (t, J=7.0Hz, 3H).

Step 3:4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (6)

Using Procedure C (Table 1) with compound 5 the title compound 6 wasobtained (133 mg, 66%) as a white solid. ¹H NMR (DMSO-d6) δ (ppm): 11.12(s, 1H), 8.99 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.45 (dd, J=7.6, 1.8 Hz,1H), 7.35-7.30 (m, 3H), 7.18 (td, J=7.4, 1.2 Hz, 1H), 7.10 (dd, J=8.0,1.4 Hz, 1H), 6.89-6.75 (m, 4H), 6.52-6.48 (m, 1H), 5.51 (d, J=6.0 Hz,1H). LRMS (ESI): (calc) 332.12 (found) 333.19 (MH)+.

Example 3N-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzamide(8) Step 1: ethyl4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzoate (7)

Title compound 4 (0.508 g, 1.48 mmol) was dissolved in formic acid (5.0mL) and the mixture was cooled at 4° C. Sodium borohydride (0.502 g) wasadded and the reaction mixture was stirred at room temperature for 90min. The mixture was diluted in water (50 mL) and solid sodiumbicarbonate was added until alkaline (pH=8-9). This mixture wasextracted twice with ethyl acetate. The combined organic extracts werewashed with water and brine, dried over sodium sulfate and evaporated.The crude was purified by flash chromatography with 10% ethyl acetate inhexanes to afford title compound 7 (408 mg, 77%) as a colorless oil.LRMS (ESI): (calc) 359.15 (found) 360.3 (MH)+.

Step 2:N-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzamide

Using Procedure C (Table 1) with compound 7 the title compound 8 (175mg, 44%) was obtained as an off-white solid. ¹H NMR (MeOD-d₄) δ (ppm):7.60 (d, J=8.4 Hz, 2H), 7.43-7.39 (m, 1H), 7.35-7.29 (m, 2H), 7.20-7.13(m, 5H), 7.09-7.05 (m, 1H), 6.94 (dd, J=8.0 Hz, 1.6 Hz, 1H), 6.02 (s,1H), 3.27 (s, 3H). LRMS (ESI): (calc) 346.13 (found) 347.28 (MH)+.

Example 4(Z)-4-(7-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(12) Step 1: 8-chloro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (9)

The 2-(2-amino-4-chlorophenylamino)benzoic acid (2.00 g, 7.63 mmol) wasmixed with diphenyl ether (5 mL). The reaction mixture was stirred at175° C. for 2 hours. The mixture was cooled down to room temperature andput directly to the column eluting with 10% to 50% ethyl acetate inhexanes to afford the title compound 9 (1.42 g, 76%) as a purple solid.

Step 2: (E)-8,11-dichloro-5H-dibenzo[b,e][1,4]diazepine (10)

A mixture of amide 9 (1.39 g, 5.70 mmol), phosphorus oxychloride (1.6mL, 17.1 mmol) and N-dimethylaniline (2.9 mL, 22.8 mmol) in benzene (10mL) was heated at reflux for 2 hours. The reaction mixture was thencooled to room temperature and excess of phosphorus oxychloride,N-dimethylaniline and benzene were removed at reduced pressure. Theresulting residue was dissolved in dioxane (20 mL) and 2 M Na₂CO₃ (30 mL0.06 mol) and then heated at 80° C. for 1 hour. The reaction mixture wascooled to room temperature and dioxane was removed at reduced pressureand the resulting aqueous solution was extracted with EtOAc (30 mL). Theorganic phase was washed with water, brine, dried (Na₂SO₄), filtered andsolvent evaporated. The resulting crude residue was purified by columnchromatography (10% ethyl acetate in hexanes) to afford title compound10 (869 mg, 58%) as an orange solid. LRMS (ESI): (calc) 262.01 (found)263.1 (MH)+.

Step 3: (Z)-ethyl4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzoate (11)

Using Procedure B (Table 1) with compound 10 the title compound 11 (610mg, 49%) was obtained as a red foam. LRMS (ESI): (calc) 376.10 (found)377.2 (MH)+. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.03, (d, J=8.2 Hz, 2H),7.73 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.21 (s,1H), 7.13 (d, J=8.4 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.95 (t, J=7.6 Hz,2H), 6.85 (d, J=6.1 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz,3H).

Step 4:(Z)-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(12)

Using Procedure C (Table 1) with compound 11 the title compound 12 (48mg, 20%) was obtained as an orange solid. ¹H NMR (DMSO-d6) δ (ppm):11.33 (s, 1H), 9.12 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz,2H), 7.46 (s, 1H), 7.40-7.36 (m, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.10 (dd,J=8.8, 2.8 Hz, 1H), 7.01-6.90 (m, 3H), 6.85 (dd, J=7.6, 1.6 Hz, 1H).LRMS (ESI): (calc) 363.08 (found) 364.2 (MH)+.

Example 5Z)-4-(benzo[b]pyrido[3,2-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide (17)Step 1: 2-chloro-N-(2-hydroxyphenyl)nicotinamide (13)

A solution of 2-chloronicotinoyl chloride (2.91 g, 16.6 mmol) in ethylacetate (50 mL) was added to a mixture of 2-aminophenol (2.00 g, 18.3mmol) and DIPEA (4.8 mL, 27.5 mmol) in ethyl acetate (50 mL) at 4° C.The reaction mixture was stirred for 1 hour. The organic mixture waswashed with water and brine then concentrated under reduced pressure.The residue was dissolved in ethanol/THF 1:1 (75 mL) and 15% sodiumhydroxide (25 mL) and the mixture was stirred at 50° C. for 45 min. Themixture was cooled down to room temperature and concentrated in vacuo toone third volume and then acidified to pH=2 with 3M HCl. The solid wasfiltered, washed with water and dried to afford title compound 13 (3.69g, 81%) as a beige solid. LRMS (ESI): (calc) 248.04 (found) 249.2 (MH)⁺.

Step 2: benzo[b]pyrido[3,2-f][1,4]oxazepin-5(6H)-one (14)

Title compound 13 (3.65 g, 14.7 mmol) was dissolved in DMF (25.0 mL) andsodium hydroxide (0.706 g, 17.7 mmol) was added. The reaction mixturewas stirred at 130° C. for 5 hours. The mixture was cooled down to roomtemperature and an ice/water mixture was added. The precipitate wasfiltered then triturated in ethanol to afford title compound 14 (1.798g, 58%) as a white solid. LRMS (ESI): (calc) 212.06 (found) 213.2 (MH)⁺.

Step 3: (E)-5-chlorobenzo[b]pyrido[3,2-f][1,4]oxazepine (15)

Using Procedure A (Table 1) with compound 14 the title compound 15 (741mg) was obtained as a yellow oil. LRMS (ESI): (calc) 230.02 (found)231.2 (MH)⁺.

Step 4: (Z)-ethyl 4-(benzo[b]pyrido[3,2-f][1,4]oxazepin-5-yl)benzoate(16)

Using Procedure B (Table 1) with compound 15 the title compound 16 (675mg, 69% for 2 steps) was obtained as a yellow foam. LRMS (ESI): (calc)344.12 (found) 345.2 (MH)⁺.

Step 5:(Z)-4-(benzo[b]pyrido[3,2-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide (17)

Using Procedure C (Table 1) with compound 16 the title compound 17 (80mg, 36%) was obtained as a yellow solid. ¹H NMR (DMSO-d6) δ (ppm): 11.39(s, 1H), 9.16 (s, 1H), 8.52 (dd, J=5.2, 2.0 Hz, 1H), 7.88 (d, J=8.4 Hz,2H), 7.84 (d, J=8.4 Hz, 2H), 7.75 (dd, J=8.0, 2.0 Hz, 1H), 7.48-7.41 (m,2H), 7.34-7.30 (m, 3H). LRMS (ESI): (calc) 331.12 (found) 332.18 (MH)+.

Example 6(Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (23)Step 1: methyl 5-fluoro-2-(2-nitrophenoxy)benzoate (18)

Methyl 5-fluoro-2-hydroxybenzoate (2.65 g, 15.6 mmo.) and1-fluoro-2-nitrobenzene (2.02 g, 14.2 mmol) were dissolved inacetonitrile (30 mL) and cesium carbonate (6.10 g, 18.7 mmol) was added.The reaction mixture was stirred at 80° C. for 60 hours. The mixture wascooled down to room temperature and poured into ethyl acetate. Thisorganic mixture was washed with water and brine, dried over sodiumsulfate, filtered and evaporated. The crude was purified by flashchromatography with 10-20% ethyl acetate in hexanes and triturated inethanol to afford the title compound 18 (3.49 g, 84%) as white solid.LRMS (ESI): (calc) 291.05 (found) 292.2 (MS)⁺.

Step 2: methyl 2-(2-aminophenoxy)-5-fluorobenzoate (19)

To a stirring solution of title compound 18 (3.48 g, 11.9 mmol) inethanol (30 mL), acetic acid (1.0 mL) and THF (10 mL) was addedpalladium on charcol 10% (0.37 g, 10% w/w). The reaction mixture wasstirred under hydrogen atmosphere for 20 hours. The catalyst wasfiltered and the filtrate was concentrated in vacuo. The residue wasdiluted with ether and this organic mixture was washed with a saturatedaqueous solution of bicarbonate, water and brine then solvent evaporatedto afford title compound 19 (2.95 g, 95%) as a beige solid. LRMS (ESI):(calc) 261.08 (found) 262.3 (MS)⁺.

Step 3: 2-fluorodibenzo[b,f][1,4]oxazepin-11(10H)-one (20)

Title compound 19 (802 mg, 3.07 mmol) was dissolved in DCM (10 mL) andthe mixture was cooled to 0° C. Trimethylaluminum 2M in toluene (1.8 mL,3.69 mmol) was added dropwise and the reaction mixture was allowed towarm to room temperature. The mixture was then heated to 45° C. for 45h. The mixture was cooled to room temperature for the slow addition ofwater. The solution was extracted with ethyl acetate then washed twicewith HCl (10%), water and saturated solution of bicarbonate. The organiclayer was then dried over sodium sulfate and concentrated in vacuo untilthe product precipitated. The solid was filtered and dried to affordtitle compound 20 (511 mg, 73%) as a white solid. LRMS (ESI): (calc)229.05 (found) 230.1 (MS)⁺.

Step 4: (E)-11-chloro-2-fluorodibenzo[b,f][1,4]oxazepine (21)

Using Procedure A (Table 1) with compound 20 the title compound 21 wasobtained (545 mg, 65%) as a yellow solid. LRMS (ESI): (calc) 247.02(found) 248.0 (MS)⁺.

Step 5: (Z)-ethyl 4-(2-fluorodibenzo[b][1,4]oxazepin-11-yl)benzoate (22)

Using Procedure B (Table 1) with compound 21 the title compound 22 wasobtained (680 mg, 86%) as a yellow foam. LRMS (ESI): (calc) 361.11(found) 362.2 (MS)⁺.

Step 6:(Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (23)

Using Procedure C (Table 1) with compound 22 the title compound 23 wasobtained (341 mg, 52%) as a yellow solid. ¹H NMR (400 MHZ, DMSO-d6) δ(ppm): 11.39 (s, 1H), 9.16 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.85 (d,J=8.8 Hz, 2H), 7.53-7.40 (m, 3H), 7.34-7.25 (m, 3H), 6.99 (dd, J=8.6,2.4 Hz, 1H). LRMS (ESI): (calc) 348.09 (found) 349.19 (MH)+.

Example 7(Z)-4-(benzo[b]pyrido[4,3-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide (29)Step 1: N-(2-(benzyloxy)phenyl)-3-fluoroisonicotinamide (24)

To a mixture of 3-fluoroisonicotinic acid (2.20 g, 15.6 mmol),2-(benzyloxy)aniline (2.84 g, 14.2 mmol) and BOP (6.94 g, 15.6 mmol) inDMF (20.0 mL) was added TEA (4.4 mL, 31.2 mmol). The reaction mixturewas stirred at room temperature for 20 min and poured into water. Theaqueous layer was extracted with ethyl acetate (2×). The combinedorganic extracts were washed with water and brine, dried over sodiumsulfate and concentrated in vacuo to a quarter volume. The resultingsolid was found to be the desired compound. The filtrate wasconcentrated in vacuo to dryness. The residue was triturated in 30%ethyl acetate in hexanes and the 2 solids were combined to affordcompound 24 (4.45 g, 97%) as a white solid. LRMS (ESI): (calc) 322.11(found) 323.2 (MH)+.

Step 2: 3-fluoro-N-(2-hydroxyphenyl)isonicotinamide (25)

Title compound 24 (4.40 g, 13.6 mmol) was dissolved in 33% HBr in AcOH(30 mL) and the reaction mixture was stirred at room temperature for 2hours. The mixture was diluted with water and solid sodium bicarbonate(until alkaline) then extracted twice with ethyl acetate. The combinedorganic extracts were washed with water and brine, dried over sodiumsulfate and concentrated in vacuo. The crude was triturated in 30% ethylacetate in hexanes to afford the title compound 25 (2.36 g, 75%) as abeige solid. LRMS (ESI): (calc) 232.06 (found) 233.1 (MH)+.

Step 3: benzo[b]pyrido[4,3-f][1,4]oxazepin-5(6H)-one (26)

Using Procedure H (Table 1) with compound 25 the title compound 26 wasobtained (1.86 g, 88%) as a brown solid. LRMS (ESI): (calc) 212.06(found) 213.1 (MH)+. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.86 (s, 1H),8.71 (s, 1H), 8.55 (d, J=4.9 Hz, 1H), 7.70 (dd, J=4.9, 0.6 Hz, 1H),7.40-7.37 (m, 1H), 7.25-7.15 (m, 3H).

Step 4: (E)-5-chlorobenzo[b]pyrido[4,3-f][1,4]oxazepine (27)

Using Procedure A (Table 1) with compound 26 the title compound 27 wasobtained (1.79 g, 92%) as a light yellow solid. LRMS (ESI): (calc)230.02 (found) 231.1 (MH)+. Step 5: (Z)-ethyl4-(benzo[b]pyrido[4,3-f][1,4]oxazepin-5-yl)benzoate (28)

Using Procedure B (Table 1) with compound 27 the title compound 28 wasobtained (2.39 g, 92%) as a light yellow solid. LRMS (ESI): (calc)344.12 (found) 345.0 (MH)+.

Step 6:(Z)-4-(benzo[b]pyrido[4,3-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide (29)

Using Procedure C (Table 1) with compound 28 the title compound 29 wasobtained (18 mg, 7%) as a yellow solid. (DMSO-d6) d(ppm) 1H, 11.41 (s,1H), 9.19 (s, 1H), 8.78 (d, J=0.4 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H),7.92-7.87 (m, 4H), 7.50-7.48 (m, 1H), 7.42-7.31 (m, 3H), 7.22 (dd,J=4.8, 0.4 Hz, 1H). LRMS (ESI): (calc) 331.32 (found) 332.15.

Example 8(Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamideStep 1: methyl 5-methoxy-2-(2-nitrophenoxy)benzoate (30)

Using Procedure I (Table 1) with methyl 2-hydroxy-5-methoxybenzoate and1-fluoro-2-nitrobenzene the title compound 30 was obtained (4.20 g, 95%)as a yellow solid. LRMS (ESI): (calc) 303.07 (found) 304.1 (MH)+. ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.02 (dd, J=8.1 Hz, 1H), 7.57 (ddd, J=8.6,7.4, 1.8 Hz, 1H), 7.42 (dd, J=2.1, 1.4 Hz, 1H), 7.30-7.29 (m, 2H), 7.23(ddd, J=8.4, 7.4, 1.1 Hz, 1H), 6.77 (dd, J=8.5, 1.1 Hz, 1H), 3.83 (s,3H), 3.64 (s, 3H).

Step 2: methyl 2-(2-aminophenoxy)-5-methoxybenzoate (31)

Using Procedure J (Table 1) with compound 30 the title compound 31 wasobtained (3.71 g, 100%) as a white solid. LRMS (ESI): (calc) 273.10(found) 274.1 (MH)+. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.27 (d, J=3.3Hz, 1H), 7.11 (dd, J=9.1, 3.2 Hz, 1H), 6.88-6.83 (m, 2H), 6.78 (dd,J=7.9, 1.7 Hz, 1H), 6.63 (dd, J=8.0, 1.4 Hz, 1H), 6.50 (ddd, J=8.0, 7.2,1.7 Hz, 1H), 4.97 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H).

Step 3: 2-methoxydibenzo[b,f][1,4]oxazepin-11(10H)-one (32)

Using Procedure K (Table 1) with compound 31 the title compound 32 wasobtained (3.00 g, 92%) as a white solid. LRMS (ESI): (calc) 241.07(found) 242.0 (MH)+. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.55 (s, 1H),7.34-7.26 (m, 2H), 7.22 (d, J=3.1 Hz, 1H), 7.19-7.09 (m, 4H), 3.76 (s,3H).

Step 4: (E)-11-chloro-2-methoxydibenzo[b,f][1,4]oxazepine (33)

Using Procedure A (Table 1) with compound 32 the title compound 33 wasobtained (1.83 g, 84%) as a light yellow solid. LRMS (ESI): (calc)259.04 (found) 260.1 (MH)+.

Step 5: (Z)-ethyl 4-(2-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzoate(34)

Using Procedure B (Table 1) with compound 33 the title compound 34 wasobtained (2.23 g, 85%) as a yellow foam. LRMS (ESI): (calc) 373.40(found) 374.1 (MH)+.

Step 6: (Z)-ethyl 4-(2-hydroxydibenzo[b,f][1,4]oxazepin-11-yl)benzoate(35)

To a stirring solution of compound 34 (1.57 g, 4.21 mmol) in DCM (30 mL)was added BBr₃ (1M in DCM, 13.0 mL, 13.0 mmol) at 4° C. drop wise andthe reaction mixture was stirred for 2 h. Ethanol (20 mL) was added andthe mixture was stirred at room temperature for 30 min. Enough MeOH toget everything soluble was added and this mixture was poured into ethylacetate (600 mL). This organic phase was washed with water and brine,dried over sodium sulfate, filtered and evaporated. The crude productwas purified by flash chromatography with 30% ethyl acetate in hexanesto afford title compound 35 (453 mg, 30%) as a beige solid. LRMS (ESI):(calc) 359.12 (found) 360.2 (MH)+.

Step 7: (Z)-ethyl4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzoate(36)

Using Procedure I (Table 1) with compound 35 the title compound 36 wasobtained (445 mg, 83%) as yellow oil. LRMS (ESI): (calc) 430.19 (found)431.4 (MH)+. ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.15-8.12 (m, 2H),7.91-7.88 (m, 2H), 7.41-7.39 (m, 1H), 7.28-7.16 (m, 5H), 6.63 (d, J=2.9Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 3.95 (t, J=5.4 Hz, 2H), 2.66 (t, J=5.4Hz, 2H), 2.25 (s, 6H), 1.41 (t, J=7.1 Hz, 3H).

Step 8:(Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide(37)

Using Procedure C (Table 1) with compound 36 the title compound 37 wasobtained (38 mg, 27%) as yellow solid. ¹H NMR (400 MHz, MeOH-d4) δ(ppm): 7.91-7.86 (m, 4H), 7.42-7.39 (m, 1H), 7.32-7.21 (m, 5H), 6.70 (d,J=3.2 Hz, 1H), 4.11 (t, J=5.2 Hz, 2H), 3.12 (t, J=5.2 Hz, 2H), 2.61 (s,6H) LRMS (ESI): (calc) 417.17 (found) 418.47 (MH)+.

Example 9(Z)-N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(43) Step 1: methyl 2-(2-nitro-4-(trifluoromethyl)phenoxy)benzoate (38)

Using Procedure I (Table 1) with methyl 2-hydroxybenzoate and1-fluoro-2-nitro-4-(trifluoromethyl)benzene the title compound 38 wasobtained (1.70 g, 52%). LRMS (ESI): (calc) 341.05 (found) 342.0 (MH)+.

Step 2: methyl 2-(2-amino-4-(trifluoromethyl)phenoxy)benzoate (39)

Title compound 38 (1.70 g, 1.98 mmol), Pd (C) 10% (0.17 g, 10% w/w) andMeOH were put in a Parr-Shaker apparatus and the reaction mixture waspressurized to 55 PSI of H₂. The mixture was agitated over night. Thecatalyst was filtered and the filtrate was concentrated to afford titlecompound 39 (1.55 g, 100%) as a clear oil. LRMS (ESI): (calc) 311.08(found) 312.1 (MH)+.

Step 3: 8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11(110H)-one (40)

Using Procedure K (Table 1) with compound 39 the title compound 40 wasobtained (1.20 g, 86%). LRMS (ESI): (calc) 279.05 (found) 280.1 (MH)+.¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.73 (s, 1H), 7.80 (dd, J=7.6, 1.8Hz, 1H), 7.66 (ddd, J=8.1, 7.3, 1.8 Hz, 1H), 7.58-7.51 (m, 3H), 7.41(dd, J=8.2, 1.0 Hz, 1H), 7.36 (td, J=7.5, 1.2 Hz, 1H).

Step 4: (E)-11-chloro-8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepine (41)

Using Procedure A (Table 1) with compound 40 the title compound 41 wasobtained (0.83 g, 65%). LRMS (ESI): (calc) 297.02 (found) 298.1 (MH)+.

Step 5: (Z)-ethyl4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzoate (42)

Using Procedure B (Table 1) with compound 41 the title compound 42 wasobtained (0.82 g, 72%). LRMS (ESI): (calc) 411.11 (found) 412.4 (MH)+.

Step 6:(Z)-N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(43)

Using Procedure C (Table 1) with compound 42 the title compound 43 wasobtained (0.166 g, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.38 (s,1H), 9.17 (s, 1H), 7.95-7.84 (m, 4H), 7.76 (d, J=1.6 Hz, 1H), 7.72-7.64(m, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.21 (dd, J=7.7 and 1.4 Hz, 1H) LRMS (ESI): (calc.) 398.1(found) 399.2 (MH)+.

Example 10(Z)-5-(4-(hydroxycarbamoyl)phenyl)benzo[b]pyrido[4,3-f][1,4]oxazepine2-oxide (45) Step 1: N-(2-(benzyloxy)phenyl)-3-fluoroisonicotinamide(44)

To a stirring solution of compound 28 (0.37 g, 1.08 mmol) in DCM (5.0mL) was added methyltrioxorhenium (0.027 g, 0.107 mmol) and the mixturewas stirred for 5 min. Hydrogen peroxide (35% w, 0.11 mL, 1.29 mmol) wasadded and the reaction mixture was stirred at room temperature for 2 h.The mixture was concentrated in vacuo and the crude was purified byflash chromatography with 75% ethyl acetate in hexanes to afford titlecompound 44 (0.132 g, 34%) as a yellow oil. LRMS (ESI): (calc) 360.11(found) 361.3 (MH)+. ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.50-8.49 (m, 1H),8.17-8.12 (m, 3H), 7.92-7.89 (m, 2H), 7.49-7.46 (m, 1H), 7.36-7.29 (m,3H), 7.24-7.22 (m, 1H), 4.40 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).

Step 2:(Z)-5-(4-(hydroxycarbamoyl)phenyl)benzo[b]pyrido[4,3-f][1,4]oxazepine2-oxide (45)

Using Procedure C (Table 1) with compound 44 the title compound 45 wasobtained (13 mg, 35%). ¹H NMR (400 MHz, MeOH-d₄) δ (ppm): 8.51 (d, J=1.8Hz, 1H), 8.18 (dd, J=6.8, 1.8 Hz, 1H), 7.94-7.89 (m, 4H), 7.51-7.49 (m,1H), 7.37-7.31 (m, 3H), 7.26 (d, J=6.7 Hz, 1H). LRMS (ESI): (calc)347.09 (found) 348.1 (MH)+.

Example 11 (49) Step 1: (E)-11-chlorodibenzo[b,f][1,4]thiazepine (46)

Using Procedure A (Table 1) with dibenzo[b,f][1,4]thiazepin-11(10H)-onethe title compound 46 was obtained.

Step 2: (Z)-ethyl 4-(dibenzo[b,f][1,4]thiazepin-11-yl)benzoate (47)

Using Procedure B (Table 1) with compound 46 the title compound 47 wasobtained (1.60 g, 81%) as a yellow foam. LRMS (ESI): (calc) 359.10(found) 360.3 (MH)+.

Step 3: (48)

Periodic acid (1.30 g, 5.71 mmol) was added to acetonitrile (30 mL) andthe mixture was stirred for 30 min. Chromium(VI) oxide (0.091 g, 0.91mmol) was added and the mixture was stirred for 5 min. This abovemixture was added to a solution of compound 47 (0.684 g, 1.90 mmol) inacetonitrile (20 mL). The reaction mixture was stirred at roomtemperature for 1 h. The solid was filtered and washed withacetonitrile. The filtrate was concentrated to a volume of 20 mL andethyl acetate was added. This organic phase was washed with water andbrine, dried over sodium sulfate, filtered and concentrated. The crudewas purified by flash chromatography with 10% to 30% ethyl acetate inhexanes to afford title compound 48 (545 mg, 73%) as a yellow solid.LRMS (ESI): (calc) 391.09 (found) 392.2 (MH)+. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 8.13-8.10 (m, 3H), 8.01 (dd, J=8.0, 1.4 Hz, 1H), 7.94-7.78 (m,5H), 7.65 (dd, J=8.0, 1.0 Hz, 1H), 7.57 (dd, J=7.5, 1.3 Hz, 1H), 7.52(ddd, J=8.3, 7.2, 1.4 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0Hz, 3H).

Step 4: (49)

Using Procedure C (Table 1) with compound 48 the title compound 49 wasobtained (365 mg, 71%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 11.42 (s, 1H), 9.20 (s, 1H), 8.13-8.10 (m, 1H), 7.99(dd, J=8.0, 1.2 Hz, 1H), 7.93-7.83 (m, 6H), 7.81-7.77 (m, 1H), 7.63 (dd,J=8.0, 0.8 Hz, 1H), 7.59-7.57 (m, 1H), 7.53-7.49 (m, 1H). LRMS (ESI):(calc) 378.40 (found) 379.1 (MH)+.

55: Example 12 Example 12(Z)-4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (55)Step 1: methyl 2-(5-chloro-2-nitrophenoxy)benzoate (50)

Using Procedure I (Table 1) with 4-chloro-2-fluoro-1-nitrobenzene andmethyl 2-hydroxybenzoate the title compound 50 was obtained (4.40 g,100%) as red oil. LRMS (ESI): (calc) 307.02 (found) 308.2 (MH)+.

Step 2: methyl 2-(2-amino-5-chlorophenoxy)benzoate (51)

A mixture of compound 50 (4.40 g, 14.30 mmol) and SnCl₂.2H₂O (16.13 g,71.5 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 h. Water andsaturated bicarbonate solution (˜250 ml) was added (very effervescent).The reaction mixture was diluted with ethyl acetate and then Celite® wasadded and the mixture was stirred for 15 min then filtered. The filtratewas extracted with ethyl acetate twice, and the organic extract wasdried over Na₂SO₄, filtered and concentrated. The crude was purified byflash chromatography, dry loaded with THF onto 80 g SiO₂ and eluted with0% to 50% ethyl acetate in hexanes to afford title compound 51 (2.10 g,51%) as a beige solid. LRMS (ESI): (calc) 277.05 (found) 278.2 (MH)+. ¹HNMR (400 MHz, CDCl₃) δ (ppm): 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.46 (ddd,J=7.9, 7.4, 1.8 Hz, 1H), 7.17 (td, J=7.6, 1.2 Hz, 1H), 6.97 (dd, J=8.3,0.9 Hz, 1H), 6.94 (dd, J=8.4, 2.3 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.73(d, J=8.4 Hz, 1H), 4.05 (s, 2H), 3.87 (s, 3H).

Step 3: 7-chlorodibenzo[b,f][1,4]oxazepin-11 (10H)-one (52)

Using Procedure K (Table 1) with compound 51 the title compound 52 wasobtained (1.60 g, 86%). LRMS (ESI): (calc) 245.02 (found) 246.0 (MH)+.

Step 4: (E)-7,11-dichlorodibenzo[b,f][1,4]oxazepine (53)

Using Procedure A (Table 1) with compound 52 the title compound 53 wasobtained (1.00 g, 93%) as a white solid.

Step 5: (Z)-ethyl 4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)benzoate(54)

Using Procedure B (Table 1) with compound 53 the title compound 54 wasobtained (0.50 g, 39%). LRMS (ESI): (calc) 377.08 (found) 377.7 (MH)+.

Step 6:(Z)-4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide (55)

Using Procedure C (Table 1) with compound 54 the title compound 55 wasobtained (0.21 g, 82%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.37 (s,1H), 9.16 (s, 1H), 7.87 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H),7.70-7.64 (m, 1H), 7.52-7.41 (m, 3H), 7.38-7.28 (m, 2H), 7.22-7.17 (m,1H). LRMS (ESI): (calc) 364.06 (found) 365.1 (MH)+.

Example 13 Compound (57) Step 1: Compound (56)

To a stirring solution of title compound 47 (0.359 g, 1.0 mmol) in DCM(5.0 mL) was added AcOH (5.0 mL) and oxygen peroxide (2.5 mL, excess)and the reaction mixture was stirred 20 h at room temperature. Thereaction mixture was cooled to room temperature and diluted with ethylacetate. This organic phase was washed with a saturated solution ofbicarbonate (2 times) and brine (1 time), dried over sodium sulfate,filtered and evaporated. The crude product was purified by flashchromatography with 20-30% ethyl acetate in hexanes to afford titlecompound 56 (345 mg, 92%) as yellow solid. LRMS (ESI): (calc) 375.09(found) 376.4 (MH)+.

Step 2: (57)

Using Procedure C (Table 1) with compound 56 the title compound 57 wasobtained (27 mg, 16%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.42 (s, 1H), 9.20 (s, 1H), 7.91-7.80 (m, 6H), 7.64-7.47 (m,4H), 7.41 (d, J=7.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H). LRMS (ESI): (calc)362.07 (found) 363.3 (MH)+.

Example 14(Z)-N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(64) Step 1: methyl 2-hydroxy-4-(trifluoromethyl)benzoate (58)

2-Hydroxy-4-(trifluoromethyl)benzoic acid (5.0 g, 24.26 mmol),hydrochloric acid (0.2 mL, 2.40 mmol), sulfuric acid (1.5 mL, 28.1 mmol)and methanol (40 mL) were mixed together and the reaction mixture wasstirred at 80° C. over night. The mixture was concentrated and reloaded,stirred at 100° C. overnight. More H₂SO₄ was added (heated to 100° C.overnight). The mixture was concentrated and ether was added. Theorganic layer was washed with water twice, saturated solution ofbicarbonate then brine, dried over Na₂SO₄, filtered and concentrated.The residue was dissolved in 20 ml Et₂O and filtered (to remove startingmaterial) and the filtrate was evaporated to afford title compound 58(3.9 g, 73%) as a clear oil.

Step 2: methyl 2-(2-nitrophenoxy)-4-(trifluoromethyl)benzoate (59)

Using Procedure I (Table 1) with compound 58 the title compound 59 wasobtained (4.8 g, 87%) as white solid. LRMS (ESI): (calc) 341.05 (found)342.3 (MH)+.

Step 3: methyl 2-(2-aminophenoxy)-4-(trifluoromethyl)benzoate (60)

Using Procedure J (Table 1) with compound 59 the title compound 60 wasobtained (3.9 g, 89%) as brown oil. LRMS (ESI): (calc) 311.08 (found)312.3 (MH)+.

Step 4: 3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (61)

Using Procedure K (Table 1) with compound 60 the title compound 61 wasobtained (2.7 g, 77%) as white solid. LRMS (ESI): (calc) 279.05 (found)280.2 (MH)+.

Step 5: (E)-11-chloro-3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepine (62)

Using Procedure A (Table 1) with compound 61 the title compound 62 wasobtained (1.1 g, 72%) as yellow solid. LRMS (ESI): (calc) 297.02 (found)298.2 (MH)+.

Step 6: (Z)-ethyl4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzoate (63)

Using Procedure B (Table 1) with compound 62 the title compound 63 wasobtained (1.0 g, 66%). LRMS (ESI): (calc) 411.11 (found) 412.4 (MH)+.

Step 7:(Z)-N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(64)

Using Procedure C (Table 1) with compound 63 the title compound 64 wasobtained (0.38 g, 75%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.39 (s, 1H), 9.17 (s, 1H), 7.94-7.82 (m, 5H), 7.66 (d, J=7.8HZ, 1H), 7.48-7.39 (m, 3H), 7.36-7.28 (m, 2H). LRMS (ESI): (calc) 398.09(found) 399.4 (MH)+.

Example 15(E)-N-hydroxy-4-(11-morpholinodibenzo[b,f][1,4]oxazepin-2-yl)benzamide(71) Step 1: methyl 5-bromo-2-(2-nitrophenoxy)benzoate (65)

Using Procedure I (Table 1) with methyl 5-bromo-2-hydroxybenzoate and1-fluoro-2-nitrobenzene the title compound 65 was obtained (3.12 g, 67%)as a yellow oil. LRMS (ESI): (calc) 350.97 (found) 354.2 (MH)+.

Step 2: 4′-ethyl 3-methyl 4-(2-nitrophenoxy)biphenyl-3,4′-dicarboxylate(66)

Using Procedure B (Table 1) with compound 65 the title compound 66 wasobtained (2.16 g, 58%) as a beige solid. LRMS (ESI): (calc) 421.12(found) 422.4 (MH)+.

Step 3: 4′-ethyl 3-methyl 4-(2-aminophenoxy)biphenyl-3,4′-dicarboxylate(67)

Using Procedure J (Table 1) with compound 66 the title compound 67 wasobtained (1.98 g, 100%) as a yellow oil. LRMS (ESI): (calc) 391.14(found) 392.5 (MH)+.

Step 4: ethyl4-(11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl)benzoate (68)

Using Procedure K (Table 1) with compound 67 the title compound 68 wasobtained (0.58 g, 26%) as a beige solid. LRMS (ESI): (calc) 359.12(found) 360.4 (MH)+.

Step 5: (E)-ethyl 4-(11-chlorodibenzo[b,f][1,4]oxazepin-2-yl)benzoate(69)

Using Procedure A (Table 1) with compound 68 the title compound 69 wasobtained and used crude for next step.

Step 6: (E)-ethyl4-(11-morpholinodibenzo[b,f][1,4]oxazepin-2-yl)benzoate (70)

To a stirring solution of title compound 69 (285 mg, 0.754 mmol) intoluene (5.0 mL) was added morpholine (1.00 g, 11.48 mmol) and thereaction mixture was stirred at 130° C. for 4 h. It was cooled to roomtemperature and diluted with ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude was purified by flash chromatographywith 10%-30% ethyl acetate in hexanes to afford title compound 70 (223mg, 69%) as a white solid. LRMS (ESI): (calc) 428.17 (found) 429.5(MH)+. ¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.09 (d, J=8.6 Hz, 2H), 7.84(dd, J=8.4, 2.3 Hz, 1H), 7.71-7.69 (m, 3H), 7.40 (d, J=8.4 Hz, 1H),7.17-7.01 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 3.90-3.75 (m, 4H), 3.60-3.48(m, 4H), 1.40 (t, J=7.1 Hz, 3H).

Step 7:(E)-N-hydroxy-4-(1-morpholinodibenzo[b,f][1,4]oxazepin-2-yl)benzamide(71)

Using Procedure C (Table 1) with compound 70 the title compound 71 wasobtained (74 mg, 35%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.28 (s, 1H), 9.08 (s, 1H), 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.83(d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.68 (d, J=2.4 Hz, 1H), 7.47(d, J=8.4 Hz, 1H), 7.22 (dd, J=8.0, 1.2 Hz, 1H), 7.12-7.06 (m, 2H),7.03-6.99 (m, 1H), 3.08-3.07 (m, 4H), 3.55-3.54 (m, 4H). LRMS (ESI):(calc) 415.15 (found) 416.6 (MH)+.

Example 16(Z)-N-hydroxy-4-(2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)benzamide(77) Step 1:2-(benzyloxy)-N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)benzamide (72)

To a stirring solution of 2-(benzyloxy)benzoic acid (2.55 g, 11.19 mmol)and oxalyl chloride (2.84 g, 22.39 mmol) in THF (20 mL) was added a fewdrops of DMF (0.012 mL, 0.153 mmol) at 0° C. The reaction mixture wasallowed to warm to room temperature and further stirred 30 minutes,diluted with toluene and then solvent evaporated. The residue was takenup in THF (20 mL) and to this solution was added2-chloro-6-(trifluoromethyl)pyridin-3-amine (2.0 g, 10.18 mmol) at 0° C.followed by the addition of triethylamine (4.68 mL, 33.6 mmol). Thereaction mixture was allowed to stir 3 days at room temperature thenquenched with saturated bicarbonate solution, extracted with EtOAc andsolvent evaporated to afford title compound 72 (3.0 g, 73% yield) afterpurification by flash chromatography (0 to 100% ethyl acetate inhexane). LRMS (ESI): (calc) 406.07 (found) 407.4 (MH)+.

Step 2: N-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-2-hydroxybenzamide(73)

Using Procedure L (Table 1) with compound 72 the title compound 73 wasobtained (1.54 g, 82%) as a white solid. LRMS (ESI): (calc) 316.02(found) 317.2 (MH)+.

Step 3: 2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepin-6(5H)-one(74)

To a stirring solution of title compound 73 (0.76 g, 2.4 mmol) intetraglyne (10 mL) was added sodium methoxide (0.220 g, 4.08 mmol) andthe reaction mixture was stirred at 220° C. for 3 h. The reactionmixture was cooled to room temperature diluted with water (25 mL),stirred for 20 min then filtered to give a light brown solid which waspurified by flash chromatography (0% to 60% ethyl acetate in hexanes) toafford title compound 74 (0.37 g, 55%). LRMS (ESI): (calc) 280.05(found) 281.3 (MH)+.

Step 4:(E)-6-chloro-2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepine (75)

Using Procedure A (Table 1) with compound 74 the title compound 75 (0.32g, 50%) was obtained as a yellowish solid.

Step 5: (Z)-ethyl4-(2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)benzoate(76)

Using Procedure B (Table 1) with compound 75 the title compound 76 (220mg, 25%) was obtained as a yellow solid. LRMS (ESI): (calc) 412.10(found) 413.4 (MH)+.

Step 6:(Z)-N-hydroxy-4-(2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)benzamide(77)

Using Procedure C (Table 1) with compound 76 the title compound 77 (31mg, 13%) was obtained as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.43 (s, 1H), 9.20 (s, 1H), 8.18 (d, J=8.1 Hz, 1H), 7.97-7.86(m, 5H), 7.78-7.72 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.40 (t, J=7.6 Hz,1H), 7.29 (d, J=6.6 Hz, 1H). LRMS (ESI): (calc) 399.08 (found) 400.4(MH)+.

Example 17(Z)-4-(11-cyclopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide(84a) Example 18b(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxy-N-methylbenzamide(84c) Step 1: N-cyclopropyl-2-nitroaniline (78)

Using Procedure I (Table 1) with 1-fluoro-2-nitrobenzene the titlecompound 78 (18 g, 100%) was obtained as an orange oil.

Step 2: N1-cyclopropylbenzene-1,2-diamine (79)

Using Procedure N (Table 1) with compound 78 the title compound 79 (1.9g, 76%) was obtained as a dark brown oil.

Step 3: 2-chloro-N-(2-(cyclopropylamino)phenyl)nicotinamide (80a)

Using Procedure G (Table 1) with compound 79 the title compound 80a (1.7g, 55%) was obtained as a white solid. LRMS (ESI): (calc) 287.08 (found)288.1 (MH)+.

Step 4:11-cyclopropyl-6,11-dihydro-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-one(81a)

To a solution of title compound 80a (1.9 g, 6.6 mmol) in pyridine (60mL) was added washed sodium hydride (0.8 g, 19.8 mmol, 60% in oil).Bubbling occurred and the clear solution turn yellow. The mixture washeated to 80° C. for 1 h and overnight at room temperature. It was thenheated to 120° C. for 1 h (the mixture turned black). The mixture wascooled down to room temperature and 1N HCl (20 mL) was added slowly.This mixture was extracted with DCM (2×). The combined organic extractswere dried over sodium sulfate, filtered and concentrated. The crude waspurified by flash chromatography (SiO2, 0% to 50% ethyl acetate inhexanes over 20 min then 50% for 10 min) to afford the title compound81a (1.12 g, 68%) as a beige solid.

Step 5:(E)-5-chloro-11-cyclopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepine(82a)

Using Procedure A (Table 1) with compound 81a the title compound 82a(0.25 g, 93%) was obtained. LRMS (ESI): (calc) 269.07 (found) 270.2(MH)+.

Step 6: (Z)-ethyl4-(11-cyclopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzoate(83a)

Using Procedure B (Table 1) with compound 82a the title compound 83a(164 mg, 62%) was obtained as a yellow solid. LRMS (ESI): (calc) 383.16(found) 384.4 (MH)+.

Step 7:(Z)-4-(11-cyclopropyl-1H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide(84a)

Using Procedure C (Table 1) with compound 83a the title compound 84a (31mg, 13%) was obtained as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 11.33 (s, 1H), 9.16 (s, 1H), 8.50-8.46 (m, 1H), 7.83 (d, J=8.2Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.45-7.41 (m, 1H), 7.36 (d, J=8.0 Hz,1H), 7.27-7.21 (m, 2H), 7.20-7.11 (m, 2H), 3.05-3.48 (m, 1H), 0.95-0.80(m, 2H), 0.51-0.45 (m, 1H), 0.31-0.23 (m, 1H). LRMS (ESI): (calc) 370.14(found) 371.2 (MH)+.

Step 8:(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxy-N-methylbenzamide(84c)

To a solution of title compound 83b (0.5 g, 1.307 mmol) in THF (5 mL)and MeOH (5 mL) was added an aqueous solution of lithium hydroxide (2.5mL, 5 mmol). The mixture was stirred for 2 h at room temperature thendiluted with DCM and 1N HCl and extracted with DCM. The combined organiclayers were dried over Na₂SO₄, filtered and solvent evaporated to affordthe acid intermediate. LRMS (ESI): (calc) 354.14 (found) 355.4 (MH)+.

To a solution of the acid intermediate (0.3 g, 0.846 mmol) in DMF (5 mL)was added BOP (0.412 g, 0.931 mmol) and triethylamine (0.354 mL, 2.54mmol). The mixture was stirred for 15 min then N-methylhydroxylaminehydrochloride (0.106 g, 1.270 mmol) was added. The mixture was stirredfor 1 h, poured into water and the resulting solid was filtered thenpurified by Phenomenex column (50 to 100% MeOH in H₂O) to afford titlecompound 84c (92 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.10 (s,1H), 7.66 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.52 (t, J=7.2 Hz,1H), 7.45 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.23 to 7.15 (m,2H), 7.14 to 7.06 (m, 2H), 6.94 (d, J=7.8 Hz, 1H), 3.44 to 3.35 (m, 1H),0.9 to 0.6 (m, 2H), 0.50 to 0.40 (m, 1H), 0.35 to 0.27 (m, 1H). LRMS(ESI): (calc) 354.14 (found) 355.4 (MH)+.

Example 18a(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(84b)

Following the same procedures as for compound 84a (example 17) exceptfor step 4.

Step 4: 5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (81b)

A solution of compound 83b (0.84 g, 3.11 mmol) and KHMDS (13.67 g, 6.84mmol, 0.5M in toluene) was heated to 140° C. overnight. The mixture wascooled to room temperature and water was added. This mixture wasextracted with a mixture of ethyl acetate and THF twice. The organicswere washed with brine and dried over Na₂SO₄, filtered and evaporated.The residue was triturated with DCM then purified by flashchromatography (SiO₂, 0% to 50% ethyl acetate in hexanes over 30 min) toafford title compound 81b (0.45 g, 57%) as a beige solid. LRMS (ESI):(calc) 369.15 (found) 370.5 (MH)+.

Example 19 (Z)-4-(5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(89) Step 1: 7-chloro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (85)

Using Procedure F (Table 1) with 2-(2-amino-5-chlorophenylamino)benzoicacid the title compound 85 (7.45 g, 80%) was obtained as a light brownsolid. LRMS (ESI): (calc) 244.04 (found) 245.2 (MH)+.

Step 2: 5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (86)

A suspension of title compound 85 (1.75 g, 7.15 mmol) in a solution ofsodium formate (2.43 g, 35.8 mmol) in water (32 mL) was stirred at 50°C. for 8 hours and then at room temperature. The reaction mixture wasfiltered and the resulting solid was dissolved in THF (20 mL), dilutedwith ethyl acetate (200 mL) then filtered through Celite® andconcentrated. The crude residue was triturated in 30% ethyl acetate inhexanes to afford title compound 86 (1.17 g, 78%) as a yellow solid.LRMS (ESI): (calc) 210.08 (found) 211.2 (MH)+. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 9.84 (s, 1H), 7.84 (s, 1H), 7.67 (dd, J=7.9, 1.7 Hz, 1H), 7.33(ddd, J=8.1, 7.2, 1.8 Hz, 1H), 7.00-6.86 (m, 6H).

Step 3: (E)-11-chloro-5H-dibenzo[b,e][1,4]diazepine (87)

Using Procedure A (Table 1) with 86 the title compound 87 (1.125 g, 90%)was obtained as an orange oil. LRMS (ESI): (calc) 228.05 (found) 229.2(MH)+.

Step 4: (Z)-ethyl 4-(5H-dibenzo[b,e][1,4]diazepin-11-yl)benzoate (88)

Using Procedure B (Table 1) with 87 the title compound 88 (0.954 g, 57%)was obtained as an orange solid. LRMS (ESI): (calc) 342.14 (found) 343.5(MH)+.

Step 5: (Z)-4-(5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(89)

Using Procedure C (Table 1) with 88 the title compound 89 (14 mg, 3%)was obtained as an orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):11.33 (s, 1H), 9.13 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz,2H), 7.39-7.34 (m, 2H), 7.16 (dd, J=7.6, 1.6 Hz, 1H), 7.09-6.91 (m, 5H),7.85 (dd, J=7.6, 1.2 Hz, 1H). LRMS (ESI): (calc) 329.12 (found) 330.4(MH)+.

Example 20(Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide(94) Step 1: 4-fluoro-2-methoxy-1-(2-nitrophenoxy)benzene (90)

Using Procedure I (Table 1) with 1-fluoro-2-nitrobenzene and4-fluoro-2-methoxyphenol the title compound 90 (9.32 g, 100%) wasobtained as yellow oil. LRMS (ESI): (calc) 263.06 (found) 264.3 (MH)+.

Step 2: 2-(4-fluoro-2-methoxyphenoxy)aniline (91)

To a solution of title compound 90 (9.32 g, 35.4 mmol) in MeOH (30 mL)and water (5 mL) was added ammonium chloride (3.79 g, 70.8 mmol) andzinc chloride (20.83 g, 319 mmol) and the reaction mixture was heated toreflux for 2 hours. The mixture was cooled to room temperature andfiltered and the solvent removed. The residue was diluted with ethylacetate and water and the organic phase was washed well with water,dried over Na₂SO₄, filtered and concentrated to afford title compound 91(8.3 g, 100%). LRMS (ESI): (calc) 233.09 (found) 234.1 (MH)+.

Step 3: methyl 4-(2-(4-fluoro-2-methoxyphenoxy)phenylcarbamoyl)benzoate(92)

To a slurry of title compound 91 (4 g, 17.15 mmol) and methyl4-(chlorocarbonyl)benzoate (3.58 g, 18.01 mmol) in benzene (60 mL) at 0°C. was added pyridine (4.85 mL, 60.0 mmol) drop wise followed by asingle crystal of DMAP. The temperature was raised to room temperatureand the reaction mixture was left to stir for 1 h. The reaction mixturewas filtered and the filtrate was diluted with 5% aq HCl and ethylacetate. The organic layer was washed with 5% aq HCl, water and brinethen left in the fridge over the weekend. The precipitated solid wasfiltered, washed with water and hexanes to afford title compound 92(6.38 g, 94%) as an off-white solid. LRMS (ESI): (calc) 395.12 (found)396.4 (MH)+.

Step 4: (Z)-methyl4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzoate (93)

A stirring mixture of title compound 92 (2 g, 5.06 mmol) inpolyphosphoric acid (4.76 ml, 41.7 mmol) was heated at 130° C. for 3 h.The reaction mixture was cooled, diluted with dichloromethane and waterand stirred overnight. The layers were separated and the aqueous layerwas extracted with dichloromethane. The combined organic layers werewashed with brine, dried over MgSO₄, filtered and solvent evaporated.The crude residue was purified via ISCO (0-25% Hex/EtOAc; 40 g silicagel column) to afford title compound 93 (125 mg, 6.5%) as a light yellowsolid. LRMS (ESI): (calc) 377.11 (found) 378.4 (MH)+.

Step 5:(Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide(94)

Using Procedure C (Table 1) with compound 93 the title compound 94 (102mg, 81%) was obtained as yellow solid. ¹H NMR (400 MHz, CD₃OD) δ (ppm):7.88 (s, 4H), 7.41 (m, 1H), 7.26 (m, 3H), 7.11 (dd, J=2.8 Hz, 10.4 Hz,1H), 6.38 (dd, J=2.8 Hz, 8.4 Hz, 1H), 3.97 (s, 3H). LRMS (ESI): (calc)378.10 (found) 377.3 (MH)−.

Example 21(Z)-N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(100) Step 1: methyl(2-(2-nitrophenoxy)phenyl)sulfane (95)

Using Procedure I (Table 1) with 1-fluoro-2-nitrobenzene and2-(methylthio)phenol the title compound 95 (9.25 g, 100%) was obtainedas yellow oil.

Step 2: 2-(2-(methylthio)phenoxy)aniline (96)

Using Procedure J (Table 1) with compound 95 the title compound 96 (5.82g, 71%) was obtained as yellow oil. LRMS (ESI): (calc) 231.07 (found)232.2 (MH)+.

Step 3: methyl 4-(2-(2-(methylthio)phenoxy)phenylcarbamoyl)benzoate (97)

Using Procedure G (Table 1) with compound 96 the title compound 97 (6.77g, 100%) was obtained as white solid. LRMS (ESI): (calc) 393.10 (found)394.5 (MH)+.

Step 4: (Z)-methyl4-(4-(methylthio)dibenzo[b,f][1,4]oxazepin-11-yl)benzoate (98)

Using Procedure U (Table 1) with compound 97 the title compound 98 (341mg, 36%) was obtained as yellow solid. LRMS (ESI): (calc) 375.09 (found)376.4 (MH)+.

Step 5: (Z)-methyl4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzoate (99)

To a stirring suspension of compound 98 (100 mg, 0.266 mmol) and iron(III) chloride (1.296 mg, 7.99 μmol) in acetonitrile (2 mL) after 5minutes was added periodic acid (66.8 mg, 0.293 mmol) in one portion.The reaction mixture was left to stir at room temperature overnight thenquenched with saturated sodium thiosulfate solution and diluted withethyl acetate. The organic layer was washed with water, brine, driedover MgSO₄, filtered and solvent evaporated. Purification via ISCO(0-40% EtOAc/Hexanes; 40 g silica gel column) afforded title compound 99(60 mg, 57%) as a yellow solid. LRMS (ESI): (calc) 391.09 (found) 392.4(MH)+.

Step 6:(Z)-N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(100)

Using Procedure C (Table 1) with compound 99 the title compound 100 (53mg, 88%) was obtained as yellow solid. ¹H NMR (400 MHz, CD₃OD) δ (ppm):8.00 (d, J=7.6 Hz, 1H), 7.87 (s, 4H), 7.52 (t, J=8 Hz, 1H), 7.46 (m,1H), 7.37 (d, J=7.6 Hz, 1H), 7.31 (m, 3H), 3.06 (s, 3H). LRMS (ESI):(calc) 392.08 (found) 391.4 (MH)−.

Example 22(E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N-hydroxybenzamide(104) Step 1: (E)-11-chlorodibenzo[b,f][1,4]oxazepine (101)

Using Procedure A (Table 1) with dibenzo[b,f][1,4]oxazepin-11(10H)-onethe title compound 101 (2.20 g, 100%) was obtained.

Step 2: (E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluorobenzaldehyde(102)

Using Procedure B (Table 1) with compound 101 the title compound 102(1.21 g, 87%) was obtained as a yellow foam. LRMS (ESI): (calc) 317.09(found) 318.4 (MH)+.

Step 3: (E)-methyl 4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluorobenzoate(103)

A mixture of compound 102 (0.59 g, 1.90 mmol), triethylamine (1.6 mL,11.48 mmol), potassium cyanide (0.061 g, 0.93) and2-hydroxy-2-methylpropanenitrile (1 mL, 10.93) in methanol (15 mL) wasstirred at 40° C. for 24 h then solvent evaporated. The resulting cruderesidue was purified on ISCO (0-100% EtOAc in Hexanes) to afford titlecompound 103 (0.364 g, 56%) as a yellow solid. LRMS (ESI): (calc) 347.10(found) 348.4 (MH)+.

Step 4:(E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N-hydroxybenzamide(104)

Using Procedure C (Table 1) with compound 103 the title compound 104(0.357 g, 55%) was obtained as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 11.47 (s, 1H), 9.28 (s, 1H), 7.93 (t, J=7.6 Hz, 1H), 7.79 (dd,J=8.4, 1.6, 1H), 7.66-7.60 (m, 2H), 7.44-7.39 (m, 2H), 7.35-7.22 (m,4H), 7.08 (d, J=7.6 Hz, 1H). LRMS (ESI): (calc) 348.09 (found) 349.3(MH)+.

Example 23 Compound (111) Step 1:4-chloro-6-(indolin-1-yl)pyrimidin-5-amine (105)

To a stirring slurry of 5-amino-4,6-dichloropyrimidine (3 g, 18.29 mmol)and indoline (2.057 mL, 18.29 mmol) in ethanol (7 mL) and water (43 mL)was added concentrated aqueous HCl (600 μL) and the mixture was refluxedfor 3 h and left to stir at room temperature overnight. The reactionmixture was extracted with ethyl acetate, washed with water, brine,dried over MgSO4 and solvent evaporated. The resulting residue wastriturated in 25% ethyl acetate in hexanes for 1 h then filtered toafford title compound 105 (1.55 g, 34%) as a tan solid. LRMS (ESI):(calc) 246.07 (found) 247.2 (MH)+.

Step 2: 4-(indolin-1-yl)pyrimidin-5-amine (106)

Using Procedure J (Table 1) with compound 105 the title compound 106(1.33 g, 100%) was obtained. LRMS (ESI): (calc) 212.11 (found) 213.1(MH)+.

Step 3: methyl 4-(4-(indolin-1-yl)pyrimidin-5-ylcarbamoyl)benzoate (107)

Using Procedure G (Table 1) with compound 106 the title compound 107(1.40 g, 60%) was obtained as a light brown solid. LRMS (ESI): (calc)374.14 (found) 375.4 (MH)+.

Step 4: Compound (108)

Using Procedure U (Table 1) with compound 107 the title compound 108(282 mg, 47%) was obtained as a red solid. LRMS (ESI): (calc) 356.13(found) 357.4 (MH)+.

Step 5: Compound (109)

A stirring suspension of compound 108 (282 mg, 0.791 mmol) andtrimethyltin hydroxide (858 mg, 4.75 mmol) in dichloroethane (5 mL) washeated at 90° C. overnight. The mixture was cooled, diluted with ethylacetate and washed with 5% aq HCl. The product precipitated out of theaqueous layer therefore it was filtered and dried to afford titlecompound 109 (155 mg, 57%) as a dark red powder. LRMS (ESI): (calc)342.11 (found) 343.4 (MH)+.

Step 6: Compound (110)

To a stirring solution of compound 109 (155 mg, 0.453 mmol) in dry DMF(15 mL) was added HATU (207 mg, 0.543 mmol) and the suspension wasstirred for 10 min at room temperature.O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (106 mg, 0.906 mmol) was addedand the resulting clear red solution was stirred for 20 min beforetriethylamine (0.150 mL, 1.076 mmol) was added. The mixture was stirredfor 16 h at room temperature, quenched with water and extracted withdichloromethane. The combined organic layers were washed with water,brine, dried over MgSO₄, filtered and solvent evaporated. The cruderesidue was purified via ISCO (50-100% EtOAc/Hexanes) to afford titlecompound 110 (87 mg, 43%) as a dark red solid. LRMS (ESI): (calc) 441.18(found) 442.5 (MH)+.

Step 7: Compound (111)

To a stirring solution of compound 110 (87 mg, 0.197 mmol) in THF (1.0mL) and water (0.5 mL) was added AcOH (1 mL). The reaction was thenheated at 80° C. overnight and then cooled to room temperature. Theproduct precipitated out and was filtered off to afford title compoundIII (16 mg, 23%) as a red powder. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):11.3 (bs, 1H), 9.12 (bs, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 7.78 (d, J=8.4Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.25 (d, J=7.2 Hz, 1H), 6.78 (t, J=7.6Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 4.00 (t, J=8.4 Hz, 2H), 2.94 (t, J=8.4Hz, 2H). LRMS (ESI): (calc) 357.12 (found) 356.4 (MH)+.

Example 24(Z)-4-(5-ethyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(115) Step 1: methyl 4-(2-(phenylamino)phenylcarbamoyl)benzoate (112)

Using Procedure G (Table 1) with N1-phenylbenzene-1,2-diamine and methyl4-(chlorocarbonyl)benzoate the title compound 112 (3.46 g, 92%) wasobtained as a red solid. LRMS (ESI): (calc) 346.13 (found) 347.4 (MH)+.

Step 2: methyl 4-(2-(ethyl(phenyl)amino)phenylcarbamoyl)benzoate (113)

To a stirring solution of compound 112 (1.00 g, 2.89 mmol) in THF wasadded dibutyltin dichloride (0.175 g, 0.577 mmol) and acetaldehyde(1.182 g, 26.8 mmol) and the reaction mixture was stirred 15 minutes.Phenylsilane (0.375 g, 3.46 mmol) was added and the reaction mixture wasstirred at room temperature 60 h then solvent evaporated. The resultingcrude product was purified by Isco (80 g column, 10%-50%) to affordtitle compound 113 (1.145 g, 100%) as a yellowish oil. LRMS (ESI):(calc) 374.16 (found) 375.4 (MH)+.

Step 3: (Z)-methyl4-(5-ethyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzoate (114)

Using Procedure U (Table 1) with compound 113 the title compound 114(353 mg, 54%) was obtained as an orange foam. LRMS (ESI): (calc) 356.15(found) 357.5 (MH)+.

Step 4:(Z)-4-(5-ethyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide(115)

Using Procedure C (Table 1) with compound 114 the title compound 115(248 mg, 72%) was obtained as a yellow solid. ¹H NMR (400 MHz, MeOH-d₄)δ (ppm): 7.83 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.49 (ddd,J=8.2, 7.2, 1.6 Hz, 1H), 7.26 (dd, J=1.6 Hz, 1H), 7.23-7.18 (m, 2H),7.13-7.03 (m, 3H), 7.96 (dd, J=7.6, 1.2, 1H), 3.83-3.68 (m, 2H), 1.24(t, J=6.8 Hz, 3H). LRMS (ESI): (calc) 357.15 (found) 358.3 (MH)+.

Example 25(E)-2-(4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide(117) Step 1: (E)-ethyl2-(4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-yl)pyrimidine-5-carboxylate(116)

A solution of (E)-2-chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine(0.25 g, 0.8 mmol) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate(0.13 g, 0.57 mmol) in DME was stirred at room temperature for 1 h. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic extract was washed with saturated aqueous solutionof bicarbonate, water, acetic acid and sodium acetate (pH=4), dried oversodium sulfate and solvent evaporated. The resulting crude residue waspurified by flash chromatography (0% to 30% ethyl acetate in hexane) toafford title compound 116 (0.265 g, quant.).

Step 2:(E)-2-(4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-yl)-N-hydroxypyrimidine-5-carboxamide(117)

Using Procedure C (Table 1) with compound 116 the title compound 117(0.2 g, 78%) was obtained as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.69 (s, 2H), 7.62 (dd, J=8.6, 2.4 Hz, 1H), 7.52 (d, J=2.3 Hz,1H), 7.41 (d, J=8.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.12-7.04 (m, 2H),7.03-6.96 (m, 1H), 4.12-3.76 (m, 4H), 3.68-3.44 (m, 4H). LRMS (ESI):(calc) 450.12 (found) 451.1 (MH)+.

Example 26(Z)-4-(benzo[f]thieno[2,3-b][1,4]oxazepin-5-yl)-N-hydroxybenzamide (124)Step 1: methyl5-(2-(methoxycarbonyl)phenoxy)-4-nitrothiophene-2-carboxylate (118)

Using Procedure I (Table 1) with methyl5-chloro-4-nitrothiophene-2-carboxylate and methyl 2-hydroxybenzoate thetitle compound 118 (1.918 g, 93%) was obtained as an orange oil. LRMS(ESI): (calc) 337.03 (found) 338.0 (MH)+.

Step 2: methyl5-oxo-4,5-dihydrobenzo[f]thieno[2,3-b][1,4]oxazepine-2-carboxylate (119)

To a stirring solution of compound 118 (1.918 g, 5.69 mmol) in aceticacid was added iron (2.223 g, 39.8 mmol) and the reaction mixture wasstirred at 85° C. for 1 h then at 100° C. for 1 h. The mixture wascooled to room temperature, poured into 150 mL of ice-cold water and theresulting white precipitate was filtered to afford title compound 119(1.261 g, 81%) as a beige solid. LRMS (ESI): (calc) 275.03 (found) 276.2(MH)+.

Step 3:5-oxo-4,5-dihydrobenzo[f]thieno[2,3-b][1,4]oxazepine-2-carboxylic acid(120)

To a stirring solution of compound 119 (0.856 g, 3.11 mmol) in ethanol(16 mL) and THF (8 mL) was added an aqueous solution of sodium hydroxide(5 mL, 31.3 mmol) and the resulting mixture was stirred at 55° C. for 2h. The reaction mixture was solvent evaporated to one third volume,acidified with 3N HCl to pH 2 and the resulting white precipitate wasfiltered to afford 120 (0.801 g, 99%) as a beige solid. LRMS (ESI):(calc) 261.01 (found) 262.1 (MH)+.

Step 4: benzo[f]thieno[2,3-b][1,4]oxazepin-5(4H)-one (121)

To a stirring solution of compound 120 (0.801 g, 3.07 mmol) in aceticacid (30 mL) was added mercuric oxide (red) (0.664 g, 3.07 mmol) and thereaction mixture was stirred at reflux for 8 hours. The mixture was thencooled to room temperature and poured into ice-cold water (75 mL). Theresulting solid was filtered and triturated in ethanol to afford titlecompound 121 (0.527 g, 79%) as a beige solid. LRMS (ESI): (calc) 217.02(found) 217.9 (MH)+. ¹H NMR (DMSO-d₆) δ (ppm): 10.45 (s, 1H), 7.80 (d,J=7.6 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.33 (t, J=7.4 Hz, 1H), 7.25 (d,J=8.0 Hz, 1H), 6.99 (d, J=6.1 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H).

Step 5: (E)-5-chlorobenzo[f]thieno[2,3-b][1,4]oxazepine (122)

Using Procedure A (Table 1) with compound 121 the title compound 122 wasobtained as a brown oil and used crude for next step.

Step 6: (Z)-ethyl 4-(benzo[f]thieno[2,3-b][1,4]oxazepin-5-yl)benzoate(123)

Using Procedure B (Table 1) with compound 122 the title compound 123(0.461 g, 55%) was obtained as a yellow foam. LRMS (ESI): (calc) 349.08(found) 350.2 (MH)+. ¹H NMR (DMSO-d₆) δ (ppm): 8.06 (d, J=8.2 Hz, 2H),7.83 (d, J=8.4 Hz, 2H), 7.70-7.66 (m, 1H), 7.35 (dd, J=8.1, 1.1 Hz, 1H),7.31 (dd, J=7.5, 1.1 Hz, 1H), 7.14 (dd, J=7.7, 1.7 Hz, 1H), 7.13 (d,J=6.1 Hz, 1H), 6.97 (dd, J=6.1, 0.4 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H),1.34 (t, J=7.1 Hz, 3H).

Step 7:(Z)-4-(benzo[f]thieno[2,3-b][1,4]oxazepin-5-yl)-N-hydroxybenzamide (124)

Using Procedure C (Table 1) with compound 123 the title compound 124(0.366 g, 83%) was obtained as a yellow solid. ¹H NMR (DMSO-d₆) δ (ppm):11.36 (s, 1H), 9.16 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz,2H), 7.70-7.65 (m, 1H), 7.35-7.31 (m, 2H), 7.16-7.12 (m, 2H), 6.96 (d,J=6.1 Hz, 1H). LRMS (ESI): (calc) 336.06 (found) 337.28 (MH)+.

TABLE 1 Proc Sc Ex Step Reaction Conditions A 1 1 1

A 4 4 2

B 1 1 2

C 1 1 3

D 2 2 2

E 3 3 1

F 4 4 1

G 5 5 1

G 19 20 3

G 7 7 1

H 5 5 2

I 17 17 1

I 6 6 1

I 8 8 7

J 6 6 2

J 12 12 2

J 19 20 2

J 18 19 2

J 22 23 2

K 6 6 3

L 7 7 2

M 8 8 6

N 9 9 2

O 10 10 1

P 11 11 3

P 13 13 1

Q 14 14 1

R 15 15 6

S 16 16 1

T 17 17 4

U 19 20 4

V 21 22 3

W 22 23 5

W 25 26 3

X 22 23 6

Y 22 23 7

Z 23 24 2

AA 24 25 1

AB 25 26 2

AC 25 26 4

The compounds of the following table of examples (Table 2) are preparedstarting from the corresponding starting material and following thepreparative sequence (general procedure A to AC) indicated.

TABLE 2 Prep- arative Ex Cpd Starting Material Structure NameCharacterization sequence  1  3

(Z)-4- (dibenzo[b,f][1,4]ox- azepin-11-yl)-N- hydroxybenzamide ¹H NMR(DMSO-d₆) δ (ppm): 11.37 (br s, 1H), 9.14 (br s, 1H), 7.86 (d, J = 8.8Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.66-7.62 (m, 1H), 7.43-7.39 (m, 2H),7.32-7.25 (m, 4H), 7.17 (dd, J = 8.0, 1.6 Hz, 1H). LRMS(ESI): (calc)330.1 (found) 331.4 (MH)+. A, B, C  2  6

4-(10,11- dihydrodibenzo[b,f] [1,4]oxazepin-11-yl)- N- hydroxybenzamide(DMSO-d6) δ (ppm): 11.12 (s, 1H), 8.99 (s, 1H), 7.65 (d, J = 8.4 Hz,2H), 7.45 (dd, J = 7.6, 1.8 Hz, 1H), 7.35- 7.30 (m, 3H), 7.18 (td, J =7.4, 1.2 Hz, 1H), 7.10 (dd, J = 8.0, 1.4 Hz, 1H), 6.89-6.75 (m, 4H),6.52-6.48 (m, 1H), 5.51 (d, J = 6.0 Hz, 1H). LRMS(ESI): (calc) 332.12(found) 333.19 (MH)+ A, B, D, C  3  8

N-hydroxy-4-(10- methyl-10,11- dihydrodibenzo[b,f] [1,4]oxazepin-11-yl)benzamide (MeOD-d4) δ (ppm): 7.60 (d, J = 8.4 Hz, 2H), 7.43-7.39 (m,1H), 7.35- 7.29 (m, 2H), 7.20-7.13 (m, 5H), 7.09-7.05 (m, 1H), 6.94 (dd,J = 8.0 Hz, 1.6 Hz, 1H), 6.02 (s, 1H), 3.27 (s, 3H). LRMS(ESI): (calc)346.13 (found) 347.28 (MH)+ A, B, E, C  4  12

(Z)-4-(8-chloro-5H- dibenzo[b,e][1,4]di- azepin-11-yl)-N-hydroxybenzamide (DMSO-d6) δ (ppm): 11.33 (s, 1H), 9.12 (s, 1H), 7.80(d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 (s, 1H), 7.40-7.36(m, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.8, 2.8 Hz, 1H),7.01-6.90 (m, 3H), 6.85 (dd, J = 7.6, 1.6 Hz, 1H). LRMS(ESI): MS (ESI):(calc) 363.08 (found) 364.22 (MH)+ F, A, B, C  5  17

(Z)-4- (benzo[b]pyrido[3,2- f][1,4]oxazepin-5- yl)-N- hydroxybenzamide(DMSO-d6) δ (ppm): 11.39 (s, 1H), 9.16 (s, 1H), 8.52 (dd, J = 5.2, 2.0Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.75 (dd, J= 8.0, 2.0 Hz, 1H), 7.48-7.41 (m, 2H), 7.34- 7.30 (m, 3H). LRMS(ESI):(calc) 331.12 (found) 332.18 (MH)+ G, H, A, B, C  6  23

(Z)-4-(2- fluorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d6) δ (ppm): 11.39 (s, 1H), 9.16 (s, 1H), 7.88 (d, J = 8.8 Hz,2H), 7.85 (d, J = 8.8 Hz, 2H), 7.53-7.40 (m, 3H), 7.34-7.25 (m, 3H),6.99 (dd, J = 8.6, 2.4 Hz, 1H). LRMS(ESI): (calc) 348.09 (found) 349.19(MH)+ I, J, K, A, B, C 7  29

(Z)-4- (benzo[b]pyrido[4,3- f][1,4]oxazepin-5- yl)-N- hydroxybenzamide(DMSO-d6) d(ppm) 1H: 11.41 (s, 1H), 9.19 (s, 1H), 8.78 (d, J = 0.4 Hz,1H), 8.55 (d, J = 4.8 Hz, 1H), 7.92- 7.87 (m, 4H), 7.50-7.48 (m, 1H),7.42-7.31 (m, 3H), 7.22 (dd, J = 4.8, 0.4 Hz, 1H) LRMS(ESI): (calc)331.32 (found) 332.15 (MH)+ G, L, H, A, B, C  8  37

(Z)-4-(2-(2- (dimethylamino)eth- oxy)dibenzo[b,f][1,4]oxazepin-11-yl)-N- hydroxybenzamide (MeOH-d4) d(ppm) 1H: 7.91-7.86 (m,4H), 7.42-7.39 (m, 1H), 7.32- 7.21 (m, 5H), 6.70 (d, J = 3.2 Hz, 1H),4.11 (t, J = 5.2 Hz, 2H), 3.12 (t, J = 5.2 Hz, 2H), 2.61 (s, 6H)LRMS(ESI): (calc) 417.17 (found) 418.47 (MH)+ I, J, K, A, B, M, I, C  9 43

(Z)-N-hydroxy-4-(8- (trifluoromethyl)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (dmso) d(ppm) 1H: 11.38 (s, 1H), 9.17 (s, 1H), 7.95-7.84(m, 4H), 7.76 (d, J = 1.6 Hz, 1H), 7.72-7.64 (m, 2H), 7.55 (d, J = 8.5Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.21 (dd, J= 7.7 and 1.4 Hz, 1H) LRMS(ESI): (calc.) 398.1 (found) 399.2 (MH)+ I, N,K, A, B, C 10  45

(Z)-5-(4- (hydroxycarbamoyl) phenyl)benzo[b] pyrido[4,3-f][1,4]oxazepine 2- oxide (MeOH-d₄) δ (ppm): 8.51 (d, J = 1.8 Hz, 1H),8.18 (dd, J = 6.8, 1.8 Hz, 1H), 7.94-7.89 (m, 4H), 7.51-7.49 (m, 1H),7.37-7.31 (m, 3H), 7.26 (d, J = 6.7 Hz, 1H). LRMS(ESI): (calc) 347.09(found) 348.1 (MH)+. G, L, H, A, B, O, C 11  49

(DMSO-d₆) δ (ppm): 11.42 (s, 1H), 9.20 (s, 1H), 8.13-8.10 (m, 1H), 7.99(dd, J = 8.0, 1.2 Hz, 1H), 7.93-7.83 (m, 6H), 7.81-7.77 (m, 1H), 7.63(dd, J = 8.0, 0.8 Hz, 1H), 7.59-7.57 (m, 1H), 7.53-7.49 (m, 1H).LRMS(ESI): (calc) 378.40 (found) 379.1 (MH)+. A, B, P, C 12  55

(Z)-4-(7- chlorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.37 (s, 1H), 9.16 (s, 1H), 7.87 (d, J = 8.3 Hz,2H), 7.82 (d, J = 8.2 Hz, 2H), 7.70-7.64 (m, 1H), 7.52-7.41 (m, 3H),7.38- 7.28 (m, 2H), 7.22-7.17 (m, 1H). LRMS(ESI): (calc) 364.06 (found)365.1 (MH)+. I, J, K, A, B, C 13  57

(DMSO-d₆) δ (ppm): 11.42 (s, 1H), 9.20 (s, 1H), 7.91-7.80 (m, 6H), 7.64-7.47 (m, 4H), 7.41 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H).LRMS(ESI): (calc) 362.07 (found) 363.3 (MH)+. A, B, P, C 14  64

(Z)-N-hydroxy-4-(3- (trifluoromethyl)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (DMSO-d₆) δ (ppm): 11.39 (s, 1H), 9.17 (s, 1H),7.94-7.82 (m, 5H), 7.66 (d, J = 7.8 HZ, 1H), 7.48-7.39 (m, 3H),7.36-7.28 (m, 2H). LRMS(ESI): (calc) 398.09 (found) 399.4 (MH)+. Q, I,J, K, A, B, C 15  71

(E)-N-hydroxy-4- (11- morpholinodibenzo [b,f][1,4]oxazepin-2-yl)benzamide (DMSO-d₆) δ (ppm): 11.28 (s, 1H), 9.08 (s, 1H), 7.90 (dd, J= 8.4, 2.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H),7.68 (d, J = 2.4 Hz, 1H) , 7.47 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.0,1.2 Hz, 1H), 7.12-7.06 (m, 2H), 7.03-6.99 (m, 1H), 3.08- 3.07 (m, 4H),3.55-3.54 (m, 4H). LRMS(ESI): (calc) 415.15 (found) 416.6 (MH)+. I, B,J, K, A, R, C 16  77

(Z)-N-hydroxy-4-(2- (trifluoromethyl)benzo [f]pyrido[2,3-b][1,4]oxazepin-6- yl)benzamide (DMSO-d₆) δ (ppm): 11.43 (s, 1H), 9.20(s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.97-7.86 (m, 5H), 7.78-7.72 (m, 1H),7.55 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 6.6 Hz,1H). LRMS(ESI): (calc) 399.08 (found) 400.4 (MH)+. S, L, H, A, B, C 17   84a

(Z)-4-(11- cyclopropyl-11H- benzo[b]pyrido[2,3- e][1,4]diazepin-5-yl)-N- hydroxybenzamide (DMSO-d₆) δ (ppm): 11.33 (s, 1H), 9.16 (s, 1H),8.50-8.46 (m, 1H), 7.83 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H),7.45-7.41 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27-7.21 (m, 2H),7.20-7.11 (m, 2H), 3.05-3.48 (m, 1H), 0.95-0.80 (m, 2H), 0.51-0.45 (m,1H), 0.31-0.23 (m, 1H). LRMS(ESI): (calc) 370.14 (found) 371.2 (MH)+. I,N, G, T, A, B, C 18a   84b

(Z)-4-(5-cyclopropyl- 5H- dibenzo[b,e][1,4]di- azepin-11-yl)-N-hydroxybenzamide (DMSO-d₆) δ (ppm): 11.31 (s, 1H), 9.14 (s, 1H), 7.81(d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.55-7.49 (m, 1H), 7.46(d, J = 7.9 Hz, 1H), 7.35-7.31 (m, 1H), 7.22-7.16 (m, 2H), 7.14-7.05 (m,2H), 6.95-6.90 (m, 1H), 3.45-3.35 (m, 1H), 0.81- 0.98 (m, 2H), 0.50-0.40(m, 1H), 0.39-0.25 (m, 1H). LRMS(ESI): (calc) 369.2 (found) 370.5 (MH)+.I, N, G, T, A, B, C 18b    84c

(Z)-4-(5-cyclopropyl- 5H- dibenzo[b,e][1,4]di- azepin-11-yl)-N-hydroxy-N- methylbenzamide (DMSO-d₆) δ (ppm): 10.10 (s, 1H), 7.66 (d, J= 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.45(d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.23-7.15 (m, 2H), 7.14-7.06 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 3.44-3.35 (m, 1H), 3.28 (s, 3H),0.9-0.6 (m, 2H), 0.50-0.40 (m, 1H), 0.35-0.27 (m, 1H). LRMS(ESI): (calc)383.16 (found) 384.5 (MH)+. I, N, G, T, A, B, W, C 19  89

(Z)-4-(5H- dibenzo[b,e][1,4]di- azepin-11-yl)-N- hydroxybenzamide(DMSO-d₆) δ (ppm): 11.33 (s, 1H), 9.13 (s,1H), 7.81 (d, J = 8.4 Hz, 2H),7.65 (d, J = 8.4 Hz, 2H), 7.39-7.34 (m, 2H), 7.16 (dd, J = 7.6, 1.6 Hz,1H), 7.09-6.91 (m, 5H), 7.85 (dd, J = 7.6, 1.2 Hz, 1H). LRMS(ESI):(calc) 329.12 (found) 330.4 (MH)+. F, J, A, B, C 20  94

(Z)-4-(2-fluoro-4- methoxydibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide (CD₃OD) δ (ppm): 7.88 (s, 4H), 7.41 (m, 1H), 7.26 (m,3H), 7.11 (dd, J = 2.8 Hz, 10.4 Hz, 1H), 6.38 (dd, J = 2.8 Hz, 8.4 Hz,1H), 3.97 (s, 3H). LRMS(ESI): (calc) 378.10 (found) 377.3 (MH)−. I, J,G, U, C 21 100

(Z)-N-hydroxy-4-(4- (methylsulfinyl)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (CD₃OD) δ (ppm): 8.00 (d, J = 7.6 Hz, 1H), 7.87 (s, 4H),7.52 (t, J = 8 Hz, 1H), 7.46 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.31 (m,3H), 3.06 (s, 3H). MS (m/z): 391.4 (M − H). I, J, G, U, P, C 22 104

(E)-4- (dibenzo[b,f][1,4]ox- azepin-11-yl)-3- fluoro-N- hydroxybenzamide(DMSO-d₆) δ (ppm): 11.47 (s, 1H), 9.28 (s, 1H), 7.93 (t, J = 7.6 Hz,1H), 7.79 (dd, J = 8.4, 1.6, 1H), 7.66-7.60 (m, 2H), 7.44-7.39 (m, 2H),7.35- 7.22 (m, 4H), 7.08 (d, J = 7.6 Hz, 1H). LRMS(ESI): (calc) 348.09(found) 349.3 (MH)+. A, B, V, C 23 111

(DMSO-d₆) δ (ppm): 11.3 (bs, 1H), 9.12 (bs, 1H), 8.29 (s, 1H), 8.02 (s,1H), 7.78 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.25 (d, J =7.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 4.00(t, J = 8.4 Hz, 2H), 2.94 (t, J = 8.4 Hz, 2H). LRMS(ESI): (calc) 357.12(found) 356.4 (MH)+. R, J, G, U, W, X, Y 24 115

(Z)-4-(5-ethyl-5H- dibenzo[b,e][1,4]di- azepin-11-yl)-N-hydroxybenzamide (DMSO-d₆) δ (ppm): 7.83 (d, J = 8.8 Hz, 2H), 7.77 (d, J= 8.8 Hz, 2H), 7.49 (ddd, J = 8.2, 7.2, 1.6 Hz, 1H), 7.26 (dd, J = 1.6Hz, 1H), 7.23-7.18 (m, 2H), 7.13-7.03 (m, 3H), 7.96 (dd, J = 7.6, 1.2,1H), 3.83-3.68 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H). LRMS(ESI): (calc)357.15 (found) 358.3 (MH)+. G, Z, U, C 25 117

(E)-2-(4-(2- chlorodibenzo[b,f] [1,4]oxazepin-11- yl)piperazin-1-yl)-N-hydroxypyrimidine- 5-carboxamide DMSO-d₆) δ (ppm): 8.69 (s, 2H), 7.62(dd, J = 8.6, 2.4 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.8Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.12- 7.04 (m, 2H), 7.03-6.96 (m,1H), 4.12-3.76 (m, 4H), 3.68-3.44 (m, 4H). LRMS(ESI): (calc) 450.12(found) 451.1 (MH)+. AA, C 26 124

(Z)-4- (benzo[f]thieno[2,3- b][1,4]oxazepin-5- yl)-N- hydroxybenzamide¹H NMR (DMSO-d₆) δ (ppm): 11.36 (s, 1H), 9.16 (s, 1H), 7.86 (d, J = 8.4Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.70-7.65 (m, 1H), 7.35-7.31 (m, 2H),7.16-7.12 (m, 2H), 6.96 (d, J = 6.1 Hz, 1H). LRMS(ESI): (calc) 336.06(found) 337.28 (MH)+. I, AB, W, AC, A, B, C 27 125

(Z)-N-hydroxy-4-(2- methoxydibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(DMSO-d6) d(ppm) 1H: 11.38 (s, 1H), 9.16 (s, 1H), 7.89 (s, 4H), 7.42-7.40 (m, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.32-7.25 (m, 3H), 7.21 (dd, J =9.2, 3.4 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 3.65 (s, 3H) LRMS(ESI):(calc) 360.36 (found) 361.09 I, J, K, A, B, C 28 126

(Z)-4- (dibenzo[b,f][1,4]ox- azepin-11-yl)-2- fluoro -N-hydroxybenzamide (DMSOD6) d(ppm) 1H: 11.12 (s, 1H), 9.32 (s, 1H),7.70-7.63 (m, 3H), 7.59-7.56 (m, 1H), 7.45-7.41 (m, 2H), 7.38-7.25 (m,4H), 7.22- 7.19 ( m, 1H) LRMS(ESI): (calc.) 348.1 (found) 349.2 (MH)+ A,B, C 29 127

(Z)-N-hydroxy-4-(3- methoxydibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(MeOH-d₄) δ (ppm): 7.85 (dd, J = 8.4 Hz, 10.2 Hz, 4H), 7.37 (m, 1H),7.23 (m, 3H), 7.02 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.77(dd, J = 2.4 Hz, 8.4 Hz, 1H), 3.86 (s, 3H). LRMS(ESI): (calc.) 360.11(found) 359.00 (M)− I, N, K, A, B, C 30 128

(Z)-3- (dibenzo[b,f][1,4]ox- azepin-11-yl)-N- hydroxybenzamide (MeOH-d₄)δ (ppm): 8.22 (t, J = 1.8 Hz, 1H), 7.96-7.86 (m, 2H), 7.60- 7.54 (m,2H), 7.45-7.40 (m, 1H), 7.36-7.32 (m, 1H), 7.28-7.16 (m, 4H), 7.10 (dd,J = 7.81.6 Hz, 1H). LRMS(ESI): (calc.) 330.3 (found) 331.4 (MH)+ A, B, C31 129

(Z)-N-hydroxy-4-(8- methyldibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(DMSO-d₆) δ (ppm): 11.38 (s, 1H), 9.17 (s, 1H), 7.89 (d, J = 8.8 Hz,2H), 7.82 (d, J = 8.8 Hz, 2H), 7.65-7.61 (m, 1H), 7.39 (dd, J = 8.4, 0.8Hz, 1H), 7.29-7.15 (m, 4H), 7.07 (ddd, J = 8.2, 2.4, 0.8, 1H), 2.29 (s,3H). ). LRMS(ESI): (calc.) 344.12 (found) 345.4 (MH)+ I, J, K, A, B, C32 130

(Z)-N-hydroxy-4-(4- methoxydibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(MeOH-d₄) δ (ppm): 7.86 (s, 4H), 7.39 (m, 1H), 7.26 (m, 414), 7.14 (t, J= 8 Hz, 1H), 6.66 (d, J = 6.8 Hz, 1H), 3.96 (s, 3H). LRMS(ESI): (calc.)360.11, (found) 359.2 (MH)− I, J, K, A, B, C 33 131

(Z)-4-(9- fluorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.40 (m, 1H), 9.20 (m, 1H), 7.88 (d, J = 7.3 Hz,2H), 7.82 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.1 Hz, 1H), 7.43 (d, J =8.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.25-7.14 (m, 3H) . LRMS(ESI): (calc.)348.3 (found) 349.4 (MH)+ I, N, K, A, B, C 34 132

(Z)-N-hydroxy-4-(7- (trifluoromethyl)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (DMSO-d₆) δ (ppm): 11.39 (s, 1H), 9.17 (s, 1H),7.93-7.82 (m, 4H), 7.76 (s, 1H), 7.72-7.58 (m, 3H), 7.53 (d, J = 8.0 Hz,1H), 7.33 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H). LRMS(ESI):(calc.) 398.09 (found) 399.1 (MH)+ I, J, K, A, B, C 35 133

(Z)-4-(2- chlorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.38 (s, 1H), 9.15 (s, 1H), 7.88 (d, J = 8.6 Hz,2H), 7.84 (d, J = 8.4 Hz, 2H), 7.71 (dd, J = 8.6, 2.5 Hz, 1H), 7.47 (d,J = 8.6 Hz, 1H), 7.45-7.70 (m, 1H), 7.36-7.26 (m, 3H), 7.18 (d, J = 2.5Hz, 1H). LRMS(ESI): (calc.) 364.06 (found) 365.3 (MH)+ I, J, K, A, B, C36 134

(Z)-4-(8- cyanodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.41 (s, 1H), 9.18 (s, 1H), 7.93-7.85 (m, 5H), 7.79(dd, J = 8.4, 2.0 Hz, 1H), 7.73-7.69 (m, 1H), 7.54 (d, J = 8.4 Hz, 1H),7.49 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.23(dd, J = 7.6, 1.6 Hz, 1H). LRMS(ESI): (calc.) 355.10 (found) 356.2 (MH)+I, J, K, A, B, C 37 135

(Z)-N-hydroxy-4-(4- methyldibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(CD₃OD) δ (ppm): 7.84 (s, 4H), 7.46 (d, J = 6.8 Hz, 1H), 7.41 (m, 1H),7.28 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 6.8 Hz, 1H), 2.55(s, 3H). LRMS(ESI): (calc.) 344.12 (found) 343.2 (MH)− I, J, K, A, B, C38 136

(Z)-N-hydroxy-4-(3- methyldibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(CD₃OD) δ (ppm: 7.85 (m, 4H), 7.38 (m, 1H), 7.24 (m, 3H), 7.17 (s, 1H),7.02 (m, 2H), 2.40 (s, 3H). LRMS(ESI): (calc.) 344.12 (found) 343.3(MH)− I, J, K, A, B, C 39 137

(Z)-4- (benzo[b]thieno[2,3- f][1,4]oxazepin-10- yl)-N- hydroxybenzamide(DMSO-d₆) δ (ppm): 11.40 (s, 1H), 9.18 (s, 1H), 7.99-7.96 (m, 3H), 7.88(d, J = 8.4 Hz, 2H), 7.41 (dd, J = 7.6, 2.0 Hz, 1H), 7.36-7.27 (m, 2H),7.18 (dd, J = 7.6, 1.2 Hz, 1H), 7.08 (d, J = 5.2 Hz, 1H). LRMS(ESI):(calc) 336.36 (found) 337.2 (MH)+ I, J, K, A, B, C 40 138

(Z)-4-(3- fluorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.39 (s, 1H), 9.17 (s, 1H), 7.88 (d, J = 8.8 Hz,2H), 7.83 (d, J = 8.8 Hz, 2 H), 7.44-7.42 (m, 2H), 7.35-7.24 (m, 4H),7.21-7.16 (td, J = 8.4 Hz, 1H). LRMS(ESI): (calc) 348.09 (found) 349.3(MH)+ I, J, K, A, B, C 41 139

(Z)-4-(8- chlorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(CD₃OD) δ (ppm): 7.86 (s, 4H), 7.61 (m, 1H), 7.41 (s, 1H), 7.35 (d, J =8 Hz, 1H), 7.26 (m, 3H), 7.18 (m, 1H). LRMS(ESI): (calc) 364.06 (found)363.3 (MH)− I, J, K, A, B, C 42 140

(Z)-4-(6- fluorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.40 (s, 1H), 9.18 (s, 1H), 7.90 (d, J = 8.4 Hz,2H), 7.84 (d, J = 8.4 Hz, 2H), 7.71-7.67 (m, 1H), 7.40 (d, J = 8.0 Hz,1H), 7.35 (td, J = 7.6, 1.2 Hz, 1H), 7.29-7.22 (m, 4H). LRMS(ESI):(calc) 348.09 (found) 349.4 (MH)+ I, J, K, A, B, C 43 141

(Z)-4-(7- cyanodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.41 (s, 1H), 9.18 (s, 1H), 7.93 (d, J = 1.6 Hz,1H), 7.90 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.77-7.70 (m,2H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.0, 0.8 Hz, 1H), 7.35 (td,J = 7.6, 1.2 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H). LRMS(ESI): (calc)355.10 (found) 356.4 (MH)+ I, J, K, A, B, C 44 142

(Z)-N-hydroxy-4-(4- hydroxydibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(CD₃OD) δ (ppm): 7.86 (s, 4H), 7.41 (m, 2H), 7.25 (m, 2H), 7.11 (m, 1H),7.02 (t, J = 8 Hz, 1H), 6.54 (m, 1H). LRMS(ESI): (calc) 346.10 (found)345.3 (MH)− I, J, K, A, B, M, C 45 143

(Z)-N-hydroxy-4-(1- methoxydibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(DMSO-d₆) δ (ppm): 11.34 (s, 1H), 9.10 (s, 1H), 7.81 (d, J = 8.4 Hz,2H), 7.70 (d, J = 8.4 Hz, 2H), 7.58 (t, J = 8.0 Hz, 1H), 7.38-7.36 (m,1H), 7.29- 7.21 (m, 3H), 7.03-6.99 (m, 2H), 3.47 (s, 3H). LRMS(ESI):(calc) 360.11 (found) 361.2 (MH)+ Q, I, J, K, A, B, C 46 144

(Z)-N-hydroxy-4- (4-(2- methoxyethoxy)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (CD₃OD) δ (ppm): 7.84 (m, 4H), 7.22-7.41 (m, 5H), 7.13(t, J = 8 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.27 (t, J = 4.4 Hz, 2H),3.88 (t, J = 4.8 Hz, 2H), 3.51 (s, 3H). LRMS(ESI): (calc) 404.14 (found)403.4 (MH)− I, J, K, A, B, M, I, C 47 145

(Z)-4-(1- fluorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.37 (s, 1H), 9.15 (s, 1H), 7.86 (d, J = 8.4 Hz,2H), 7.81 (d, J = 8.4 Hz, 2H), 7.74-7.68 (m, 1H), 7.46-7.43 (m, 1H),7.36-7.30 (m, 4H), 7.22 (t, J = 8.8 Hz, 1H). LRMS(ESI): (calc) 348.09(found) 349.4 (MH)+ I, J, K, A, B, C 48 146

(Z)-N-hydroxy-4-(4- (2- morpholinoethoxy) dibenzo[b,f][1,4]ox-azepin-11-yl) benzamide (CD₃OD) δ (ppm): 7.87 (s, 4H), 7.10- 7.40 (m,6H), 6.69 (d, J = 7.6 Hz, 1H), 4.29 (s, 2H), 3.77 (s, 4H), 2.97 (s, 2H),2.73 (s, 4H). LRMS(ESI): (calc) 459.18 (found) 458.6 (MH)− I, J, K, A,B, M, I, C 49 147

(Z)-4- (benzo[f]pyrido[2,3- b][1,4]oxazepin-6- yl)-N- hydroxybenzamide(DMSO-d₆) δ (ppm): 11.41 (s, 1H), 9.18 (s, 1H), 8.19 (dd, J = 4.4, 1.6Hz, 1H), 7.94 (dd, J = 7.6, 2.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.85(d, J = 8.4 Hz, 2H), 7.73-7.69 (m, 1H), 7.47- 7.42 (m, 2H), 7.35 (td, J= 7.8, 0.8 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H). LRMS(ESI): (calc)331.10 (found) 332.4 (MH)+ S, L, H, A, B, C 50 148

(Z)-N-hydroxy-4-(4- (methylthio)dibenzo [b,f][1,4]oxazepin-11-yl)benzamide (CD₃OD) δ (ppm): 7.86 (s, 4H), 7.42 (m, 3H), 7.26 (m,2H), 7.20 (t, J = 8 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 3.30 (s, 3H).LRMS(ESI): (calc) 376.09 (found) 375.3 (MH)− I, J, G, U, C 51 149

(Z)-N-hydroxy-4-(4- (trifluoromethyl)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (CD₃OD) δ (ppm): 7.81-7.93 (m, 5H), 7.37-7.47 (m, 3H),7.27-7.32 (m, 3H). LRMS(ESI): (calc) 398.09 (found) 397.5 (MH)− I, J, G,U, C 52 150

(Z)-4-(5H- benzo[e]pyrrolo[1,2- a][1,4]diazepin-11- yl)-N-hydroxybenzamide (DMSO-d₆) δ (ppm): 11.36 (s, 1H), 9.14 (s, 1H), 7.99(d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.40-7.38 (m, 3H),7.27-7.19 (m, 2H), 6.23-6.19 (m, 2H), 5.18 (s, 2H). LRMS(ESI): (calc)317.12 (found) 318.4 (MH)+ I, J, K, A, B, C 53 151

(Z)-N-hydroxy-4-(4- (methylsulfonyl)di- benzo[b,f][1,4] oxazepin-11-yl)benzamide (CD3OD) δ (ppm): 8.19 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.82(q, J = 9.6 Hz, 4H), 7.68 (m, 1H), 7.46 (m, 3H), 7.30 (m, 2H), 3.51 (s,3H). LRMS(ESI): (calc) 408.08 (found) 407.4 (MH)− I, J, G, U, P, C 54152

(E)-4- ((dibenzo[b,f][1,4]ox- azepin-11- ylamino)methyl)-N-hydroxybenzamide (CD₃OD) δ (ppm): 7.75 (d, J = 8.4 Hz, 2H), 7.62-7.51(m, 4H), 7.29-7.25 (m, 2H), 7.13-7.11 (m, 1H), 7.06- 6.94 (m, 3H), 4.78(s, 2H). LRMS(ESI): (calc) (calc) 359.13 (found) 360.5 (MH)+ A, R, C 55153

(Z)-N-hydroxy-4-(4- methoxy-8- (trifluoromethyl)di- benzo[b,f][1,4]oxazepin- 11-yl)benzamide (CD₃OD) δ (ppm): 7.89 (dd, J = 8.4 Hz, 12.4Hz, 4H), 7.69 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz,1H), 7.32 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 8.4 Hz, 1 , 6.71 (d, J = 8Hz, 1H), 3.98 (s, 3H). LRMS(ESI): (calc) 428.10 (found) 427.3 (MH)− G,U, C 56 154

(Z)-N-hydroxy-4-(3- morpholinodibenzo [b,f][1,4]oxazepin-11-yl)benzamide (DMSO-d₆) δ (ppm): 11.35 (s, 1H), 9.14 (s, 1H), 7.85 (d, J= 8.4 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.38-7.33 (m, 1H), 7.27-7.21(m, 3H), 6.94 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.79 (dd, J= 8.9 and 2.5 Hz, 1H), 3.74-3.68 (m, 4H), 3.30-3.23 (m, 4H). LRMS(ESI):(calc) 415.15 (found) 416.5 (MH)+ I, J, K, I, A, B, C 57 155

(Z)-N-hydroxy-4-(4- propyldibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(CD₃OD) δ (ppm): 7.84 (m, 4H), 7.47 (d, J = 7.6 Hz, 1H), 7.40 (m, 1H),7.26 (m, 3H), 7.13 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 2.93 (t,J = 7.6 Hz, 2H), 1.76 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H). LRMS(ESI):(calc) 372.15 (found) 371.4 (MH)− I, J, G, U, C 58 156

(Z)-N-hydroxy-4-(4- (trifluoromethoxy)di- benzo[b,f][1,4]oxaze-pin-11-yl)benzamide (CD₃OD) δ (ppm): 7.88 (s, 4H), 7.63 (d, J = 8.4 Hz,1H), 7.45 (m, 1H), 7.23-7.33 (m, 4H), 7.16 (d, J = 8 Hz, 1H). LRMS(ESI):(calc) 414.08 (found) 413.4 (MH)− I, J, G, U, C 59 157

(Z)-N-hydroxy-4-(6- methyldibenzo[b,f] [1,4]oxazepin-11- yl)benzamide(DMSO-d₆) δ (ppm): 11.38 (s, 1H), 9.16 (s, 1H), 7.88 (d, J = 8.4 Hz,2H), 7.81 (d, J = 8.4 Hz, 2H), 7.67-7.63 (m, 1H), 7.48 (d, J = 8.0 Hz,1H), 7.30 (td, J = 7.6, 0.8 Hz, 1H), 7.25-7.13 (m, 4H), 2.48 (s, 3H).LRMS(ESI): (calc) 344.12 (found) 345.4 (MH)+ I, J, G, U, C 60 158

(E)-6- (dibenzo[b,f][1,4]ox- azepin-11-yl)-N- hydroxynicotinamide(DMSO-d₆) δ (ppm): 11.54 (s, 1H), 9.33 (br s, 1H), 8.92 (s, 1H), 8.38(d, J = 8.2 Hz, 1H), 8.32 (dd, J = 8.0, 1.7 Hz, 1H), 7.64-7.56 (m, 1H),7.46 (d, J = 6.7 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.36-7.21 (m, 5H).LRMS(ESI): (calc) 331.10 (found) 332.4 (MH)+ S, U, C 61 159

(E)-5- (dibenzo[b,f][1,4]ox- azepin-11-yl)-N- hydroxyfuran-2-carboxamide (DMSO-d₆) δ (ppm): 11.37 (s, 1H), 9.27 (s, 1H), 7.69-7.65(m, 1H), 7.60 (dd, J = 7.6, 1.6 Hz, 1H), 7.42-7.23 (m, 7H), 7.11 (d, J =3.2 Hz, 1H). LRMS(ESI): (calc) 320.08 (found) 321.3 (MH)+ A, B, V, C 62160

(E)-5- (dibenzo[b,f][1,4]ox- azepin-11-yl)-N- hydroxythiophene-2-carboxamide ((CD₃OD)) δ (ppm): 7.63-7.55 (m, 3H), 7.34-7.29 (m, 4H),7.24-7.19 (m, 3H). LRMS(ESI): (calc) 336.06 (found) 337.4 (MH)+ A, B, V,C 63 161

(Z)-4- (dibenzo[b,f][1,4]thi- azepin-11-yl)-N- hydroxybenzamide(DMSO-d6) δ (ppm): 11.37 (s, 1H), 9.15 (s, 1H), 7.86 (d, J = 8.8 Hz,2H), 7.78 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 8.0, 1.0, 1H), 7.57-7.49(m, 2H), 7.45-7.34 (m, 3H), 7.23-7.16 (m, 2H). LRMS(ESI): (calc) 346.08(found) 347.24 (MH)+. A, B, C 64 162

(Z)-N-hydroxy-4-(5- isopropyl-5H- dibenzo[b,e][1,4]di- azepin-11-yl)benzamide (DMSO-d₆) δ (ppm): 11.35 (s, 1H), 9.15 (s, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 1H), 7.32 (d, J =7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.22-7.18 (m, 2H), 7.15-7.09 (m,2H), 7.02 (dd, J = 7.6, 1.2 Hz, 1H), 4.33-4.28 (m, 1H), 1.17 (t, J = 6.0Hz, 3H), 1.09 (t, J = 6.0 Hz, 3H). LRMS(ESI): (calc) 371.16 (found)372.5 (MH)+. I, J or N, G, T, A, B, C 65 163

(E)-4-((5- cyclopropyl-5H- dibenzo[b,e][1,4]di- azepin-11-ylamino)methyl)-N- hydroxybenzamide (DMSO-d₆) δ (ppm): 11.16 (s, 1H),8.98 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.57-7.49 (m, 1H), 7.48-7.34 (m,5H), 7.22-7.16 (m, 1H), 7.18 (t, J = 5.4 Hz, 1H), 6.88-6.82 (m, 2H),6.74- 6.68 (m, 1H), 4.65-4.50 (m, 2H), 3.40-3.30 (m, 1H), 0.95-0.83 (m,2H), 0.40-0.27 (m, 2H). LRMS(ESI): (calc) 398.17 (found) 399.5 (MH)+. I,J or N, G, T, A, R, C 66 164

(Z)-4-(4- fluorodibenzo[b,f] [1,4]oxazepin-11-yl)- N-hydroxybenzamide(DMSO-d₆) δ (ppm): 11.39 (s, 1H), 9.19 (s, 1H), 7.89 (d, J = 8.8 Hz,2H), 7.85 (d, J = 8.8 Hz, 2H), 7.66-7.62 (m, 1H), 7.48-7.46 (m, 1H),7.35-7.28 (m, 4H), 7.01 (d, J = 7.6 Hz, 1H). LRMS(ESI): (calc) 348.09(found) 349.4 (MH)+. I, J, G, U, C 67 165

(Z)-N-hydroxy-4-(5- (2-methoxyethyl)- 5H- dibenzo[b,e][1,4]di-azepin-11- yl)benzamide (DMSO-d₆) δ (ppm): 11.33 (s, 1H), 9.13 (s, 1H),7.84 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 1H),7.29-7.17 (m, 3H), 7.13-7.09 (m, 3H), 6.99 (dd, J = 7.6, 1.2, 1H),3.97-3.91 (m, 1H), 3.82-3.76 (m, 1H), 3.52-3.49 (m, 2H), 3.16 (s, 3H).LRMS(ESI): (calc) 387.16 (found) 388.5 (MH)+. I, J or N, G, T, A, B, C68 166

(E)-4-(2- (dibenzo[b,f][1,4]ox- azepin-11- ylamino)ethyl)-N-hydroxybenzamide (DMSO-d₆) δ (ppm): 8.29 (s, 0.65H, FA salt), 7.73 (d, J= 8.0 Hz, 2H), 7.63-7.59 (m, 1H), 7.50-7.45 (m, 3H), 7.32 (dd, J = 8.2,1.0 Hz, 1H), 7.29 (dd, J = 7.6, 1.0 Hz, 1H), 7.23- 7.10 (m, 4H), 3.85(t, J = 7.2 Hz, 2H), 3.18 (t, J = 7.2 Hz, 2H). LRMS(ESI): (calc) 373.14(found) 374.5 (MH)+. Q, R, C 69 167

(Z)-N-hydroxy-11- (pyridin-4- yl)dibenzo[b,f][1,4] oxazepine-8-carboxamide (MeOD) d(ppm) 1H: 8.71 (d, J = 5.9 Hz, 2H), 7.84-7.80 (m,3H), 7.71- 7.62 (m, 2H), 7.40-7.27 (m, 3H), 7.21-7.18 (m, 1H).LRMS(ESI): (calc) 331.10 (found) 332.2 (MH)+. I, Q, J, K, A, B, C 70 168

(E)-N-hydroxy-11- (4-methylpiperazin- 1- yl)dibenzo[b,f][1,4]oxazepine-8- carboxamide (MeOD) d(ppm) 1H: 7.56-7.51 (m, 1H), 7.48 (d, J= 2.1 Hz, 1H), 7.44- 7.37 (m, 2H), 7.32-7.26 (m, 2H), 7.19 (d, J = 8.3Hz, 1H), 3.58 (br s, 4H), 2.58 (br s, 4H), 2.36 (s, 3H). LRMS(ESI):(calc) 352.15 (found) 353.4 (MH)+. I, Q, J, K, A, R, C 71 169

(Z)-4-(11-ethyl-11H- benzo[b]pyrido[2,3- e][1,4]diazepin-5-yl)- N-hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.34 (br s, 1H), 9.15 (br s,1H), 8.45 (dd, J = 4.7 and 1.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.72(d, J = 8.4 Hz, 2H), 7.45 (dd, J = 7.5 and 1.8 Hz, 1H), 7.29 (dd, J =7.6 and 1.6 Hz, 1H), 7.22 (td, J = 7.7 and 13.7 Hz, 1H), 7.19-7.08 (m,3H), 4.08 (br s, 1H), 3.55 (br s, 1H), 1.15 (t, J = 6.9 Hz, 3H).LRMS(ESI): (calc) 358.14 (found) 359.2 (MH)+. I, J or N, G, T, A, B, C72 170

(Z)-4-(5-cyclopropyl- 2-fluoro-5H- dibenzo[b,e][1,4]di- azepin-11-yl)-N-hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.33 (br s, 1H), 9.13 (br s,1H), 7.83 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.49 (dd, J =9.0 and 4.9 Hz, 1H), 7.40 (td, J = 8.5 and 2.9 HZ, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.25- 7.17 (m, 2H), 7.11 (t, J = 7.0 Hz, 1H), 6.75 (dd, J = 9.0and 2.9 Hz, 1H), 3.4 (m, 1H), 0.93-0.80 (m, 2H), 0.46- 0.39 (m, 1H),0.34-0.26 (m, 1H). LRMS(ESI): (calc) 387.14 (found) 388.5 (MH)+. I, J orN, G, T, A, B, C 73 171

(Z)-N-hydroxy-4- (11-isopropyl-11H- benzo[b]pyrido[2,3-e][1,4]diazepin-5- yl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.3 (br s,1H), 9.1 (br s, 1H), 8.50 (d, J = 3.3 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H),7.78 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 6.3 Hz, 1H), 7.29 (d, J = 7.4 HZ,1H), 7.27-15 (m, 4H), 4.614.5 (m, 1H), 1.27 (d, J = 5.7 Hz, 3H), 1.14(d, J = 5.9 Hz, 3H). LRMS(ESI): (calc) 372.16 (found) 373.2 (MH)+. I, Jor N, G, T, A, B, C 75 172

(Z)-6-(4- (dibenzo[b,f][1,4]ox- azepin-11- yl)benzamidooxy)- 3,4,5-trihydroxytetrahydro- 2H-pyran-2- carboxylic acid ¹H NMR (MeOH-d₄) δ(ppm): 7.94 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.60 (ddd, J= 7.6, 7.2, 1.6 Hz, 1H), 7.43-7.41 (m, 1H), 7.35 (dd, J = 8.4, 0.8 Hz,1H), 7.30-7.22 (m, 4H), 7.15 (dd, J = 7.6, 1.6 Hz, 1H), 4.81 (d, J = 7.6Hz, 1H), 3.95 (d, J = 9.4 Hz, 1H), 3.59-3.44 (m, 3H). LRMS(ESI): (calc)506.13 (found) 507.5 (MH)+. G, U, W, G, W 76 173

(Z)-N-hydroxy-4- (11-(3- morpholinopropyl)- 11H- benzo[b]pyrido[2,3-e][1,4]diazepin-5- yl)benzamide ¹H NMR (MeOH-d₄) δ (ppm)- formate salt:8.43 (d, J = 4.3 Hz, 1H), 8.31 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.78(d, J = 8.2 Hz,(d 2H), 7.45 (d J = 7.9 Hz, 1H), 7.33 (dd, J = 7.7 and1.2 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H),7.22-7.10 (m, 2H), 4.32-4.20 (m, 1H), 3.78- 3.64 (m, 5H), 2.86-2.78 (m,2H), 2.78-2.66 (m, 4H), 2.06-1.94 (m, 2H). LRMS(ESI): (calc) 457.21(found) 458.5 (MH)+. I, J or N, G, T, A, B, C 77 174

(Z)-N-hydroxy-4- (11-(2- morpholinoethyl)- 11H- benzo[b]pyrido[2,3-e][1,4]diazepin-5- yl)benzamide ¹H NMR. (MeOH-d₄) δ (ppm)- formate salt:8.44 (d, J = 4.3 Hz, 1H), 8.32-8.24 (m, 1H), 7.85 (d, J = 8.2 Hz, 2H),7.79 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.33 (dd, J = 7.7and 1.2 Hz, 1H), 7.28 (t, J = 9.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H),7.18-7.12 (m, 2H), 4.60-4.50 (m, 1H), 3.92-3.82 (m, 1H), 3.66-3.58 (m,4H), 3.05-2.96 (m, 2H), 2.90- 2.78 (m, 4H). LRMS(ESI): (calc) 443.20(found) 444.5 (MH)+. I, J or N, G, T, A, B, C 78 175

(Z)-4-(11- cyclopropylmethyl)- 11H- benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)- N- hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm):11.34 (s, 1H), 9.14 (s, 1H), 8.43 (dd, J = 5.1 and 1.8 Hz, 1H), 7.85 (d,J = 8.3 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 7.7 and 1.8 Hz,1H), 7.27 (dd, J = 7.4 and 1.4 Hz, 1H), 7.20 (td, J = 7.4 and 1.6 Hz,1H), 7.18-7.09 (m, 3H), 4.10-4.00 (m, 1H), 3.40- 3.20 (M, 1H), 1.13-1.04(m, 1H), 0.44-0.31 (m, 2H), 0.30-0.15 (m, 2H). LRMS(ESI): (calc) 384.16(found) 385.4 (MH)+. I, J or N, G, T, A, B, C 79 176

(Z)-N-hydroxy-4-(5- (2-morpholinoethyl)- 5H- dibenzo[b,e][1,4]di-azepin-11- yl)benzamide ¹H NMR (MeOH-d₄) δ (ppm)- formate salt: 8.26 (s,1H), 7.87-7.49 (m, 4H), 7.56-7.50 (m, 1H), 7.31- 7.21 (m, 3H), 7.18-7.09(m, 3H), 7.01 (dd, J = 7.8 and 2.2 Hz, 1H), 4.12- 3.95 (m, 2H),3.60-3.55 (m, 4H), 2.99-2.83 (m, 2H), 2.82-2.70 (m, 4H). LRMS(ESI):(calc) 442.20 (found) 443.4 (MH)+. I, J or N, G, T, A, B, C

Example 1002-((1S,4S)-5-Benzhydryl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide(203) Step 1: (1S,4S)-tert-Butyl5-benzhydryl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200)

To a stirred solution of chlorodiphenylmethane (0.39 g, 1.94 mmol) inDMF (5 mL) was added (1S,4S)-diazabicyclo[2,2,1]-heptane (0.5 g, 2.52mmol), Na₂CO₃ (0.41 g, 3.88 mmol) and NaI (0.31 g, 2.04 mmol). Themixture was stirred for 2 h at 110° C., then cooled to room temperatureand diluted with 75% AcOEt in Hexanes. The mixture was washed withwater, brine, dried (Na2SO4), filtered and concentrated. The residue waspurified by silica gel column chromatography with gradient of EtOAc(0-30%) in hexanes to afford 200 (0.5 g, 71%) as a beige solid. LRMS(ESI): (calc) 364.2 (found) 365.5 (MH)+.

Step 2: (1S,4S)-2-Benzhydryl-2,5-diazabicyclo[2.2.1]heptane2HCl (201)

A solution of compound 200 (0.5 g, 1.37 mmol) in 4N HCl in dioxane (5mL) was stirred for 1 h at room temperature and then concentrated. Theresidue was purified by trituration with Et₂O and filtered to afford 201(0.24 g, 59%) as a beige solid. LRMS (ESI): (calc) 264.2 (found) 265.3(MH)+.

Steps 3: ethyl2-((1S,4S)-5-benzhydryl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxylate(202)

Title compound 201 (0.250 g, 0.741 mmol), ethyl2-(methylsulfonyl)pyrimidine-5-carboxylate (0.122 g, 0.529 mmol),potassium carbonate (0.280 g, 2.645 mmol) and DME (5 mL) were combined.The reaction mixture was stirred at 50 oC for 2 hours. The mixture wascooled down and quench with water. The aqueous layer was extracted twicewith ethyl acetate. The combined organic extracts were washed withbrine, dried over sodium sulfate, filtered and evaporated. The crude waspurified by flash chromatography eluting with 0% to 30% ethyl acetate inhexanes to afford title compound 202 (0.141 g, 64%). LRMS (ESI): (calc)414.21 (found) 415.0 (MH)+.

Step 4:((1S,4S)-5-Benzhydryl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide(203)

Title compound 202 (0.140 g, 0.338 mmol), potassium hydroxide (4M, 0.34mL), hydroxylamine (50% in water, 0.34 mL), MeOH (2 mL) and THF (2 mL)were combined and the reaction mixture was stirred for 1 hour. HCL 3Nwas added to adjust the pH to 8. After 15 minutes stirring, the solidwas filtered and well dried to afford the title compound 203 (0.107 g,79%) as a white powder. ¹H NMR (DMSO-d6) δ (ppm): 7.80 (dd, J=8.0, 2.0Hz, 1H), 7.61 (ddd, J=8.4, 6.8, 1.2 Hz, 1H), 7.46-7.41 (m, 3H),7.38-7.30 (m, 3H), 3.62 (t, J=7.2 Hz, 2H), 2.06 (t, J=7.2 Hz, 2H),1.61-1.51 (m, 4H), 1.44-1.28 (m, 4H). LRMS: (calc) 390.12 (found) 391.3(MH)+.

Example 101N-hydroxy-4-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide(210) Step 1: (2S,4R)-tert-butyl4-(tosyloxy)-2-(tosyloxymethyl)pyrrolidine-1-carboxylate (204)

(2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate(5.40 g, 25.84 mmol) and 4-methylbenzene-1-sulfonyl chloride (14.22 g,74.6 mmol) were combined in pyridine (50 mL) at 0° C. and store in therefrigerator for 3 days. The reaction mixture was concentrated to halfthe volume under vacuo and some water (300 mL) was added slowly. Themixture was stirred 1 h until a white solid formed. The solid wasfiltered and dried on the pump on high-vacuum over night. The solid wasrecrystallized from MeOH (˜20 ml) and water (few drops) to afford titlecompound 204 (6.40 g, 49%). LRMS: (calc) 525.15 (found) 426.4 (MH-Boc)⁺.

Step 2: tert-butyl 5-benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(205)

A stirring solution of title compound 204 (3 g, 5.71 mmol) andbenzylamine (1.78 mL, 16.27 mmol) in toluene (50 mL) was heated to 120°C. in a sealed tube for 18 h. The mixture was cooled down, refrigeratedfor 1 h and the PTSA formed was filtered off and rinsed with coldtoluene. The filtrate was diluted with a diluted solution of bicarbonatein water (25 mL) and extracted with ethyl acetate (×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude was purified by flash chromatography: 40 g SiO₂,0% to 100% ethyl acetate in hexanes over 30 min to afford title compound205 (0.56 g, 36%). LRMS: (calc) 288.18 (found) 289.3 (MH)+.

Step 3: 2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (206)

Using Procedure B-2 (Table 3) with compound 205 the title compound 106was obtained (0.5 g, 99%) as a beige solid foam. LRMS: (calc) 188.13(found) 189.1 (MH)+.

Step 4: ethyl4-((1R,4R)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoate (207)

A stirring solution of title compound 206 (0.5 g, 1.914 mmol) and ethyl4-fluorobenzoate (0.421 ml, 2.87 mmol) in DMSO (19.14 mL) was stirred at140° C. overnight. The mixture was cooled down and poured over a dilutedaqueous solution of bicarbonate and extracted with ethyl acetate(twice). The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and evaporated. The crude was purified by flashchromatography: 0% to 60% ethyl acetate in hexanes over 20 min on 20 gSiO₂ to afford title compound 207 (0.33 g, 51%) as beige oil. LRMS:(calc) 336.18 (found) 337.4 (MH)+.

Step 5: ethyl 4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoateformate (208)

Title compound 207 (0.32 g, 0.878 mmol) and Pd/C (0.093 g, 0.088 mmol)were combined in methanol (16.73 mL) and formic acid (0.836 mL). Thereaction mixture was stirred at reflux for 2 h. The mixture was filteredand concentrated to afford title compound 208 (0.278 g, 99%) as a clearoil. LRMS: (calc) 246.14 (found) 247.3 (MH)+.

Step 6: ethyl4-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoate (109)

To a stirring solution of title compound 208 (0.145 g, 0.496 mmol),cesium carbonate (0.485 g, 1.488 mmol),bis(tri-t-butylphosphine)palladium (0) (0.013 g, 0.025 mmol) in THF (15mL) was added 3-iodotoluene (0.083 mL, 0.645 mmol) and the resultingsuspension was placed under N₂ and stirred at 110° C. overnight. Thereaction was cooled, filtered through Celite® and washed with THF. Thefiltrate was evaporated to afford a brown residue. This residue wasdissolved in DCM and purified by chromatography: 0% to 50% ethyl acetatein hexanes over 30 minutes to afford title compound 209 (110 mg, 66%) asan oil. LRMS: (calc) 336.18 (found) 337.5 (MH)+.

Step 7:N-hydroxy-4-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide(210)

Using Procedure D-2 (Table 3) with compound 209 the title compound 210was obtained (50 mg, 47%) as grey solid. (MeOH-d₄) δ (ppm): 7.55 (d,J=8.8 Hz, 2H), 6.99 (t, J=7.6 Hz, 1H), 6.57 (d, J=8.8 Hz, 2H), 6.43 (d,J=7.5 Hz, 1H), 6.42-6.35 (m, 2H), 4.61 (s, 1H), 4.55 (s, 1H), 3.60 (t,J=9.0 Hz, 2H), 3.23 (d, J=9.0 Hz, 1H), 3.08 (d, J=8.8 Hz, 1H), 2.22 (s,3H), 2.18-2.03 (m, 2H). LRMS: (calc) 323.16 (found) 324.4 (MH)+.

Example 102N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)benzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide(214) Step 1: (1S,4S)-tert-butyl5-(5-(ethoxycarbonyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(211)

Using Procedure C-2 (Table 3) with (1S,4S)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and ethyl2-(methylsulfonyl)pyrimidine-5-carboxylate the title compound 211 wasobtained (1.11 g, 63%) as white solid. ¹H NMR (400 MHz, CDCl3) δ (ppm):8.84-8.82 (m, 2H), 5.08 (s, 1H), 4.70-4.55 (m, 1H), 4.34 (q, J=7.1 Hz,2H), 3.70-3.34 (m, 4H), 2.02-1.94 (m, 2H), 1.47-1.43 (m, 9H), 1.37 (t,J=7.1 Hz, 3H).

Step 2: ethyl2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxylate(212)

Using Procedure B-2 (Table 3) with compound 211 the title compound 212was obtained. LRMS: (calc) 248.13 (found) 249.2 (MH)+.

Step 3: ethyl2-((1S,4S)-5-(3-(trifluoromethyl)benzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxylate(213)

To a stirring suspension of title compound 212 (160 mg, 0.562 mmol) inpyridine (3 mL) was added benzoyl chloride (0.10 mL, 0.674 mmol) dropwise. The reaction mixture was stirred overnight at room temperaturethen evaporated. The crude was purified by ISCO (10% to 90% ethylacetate in hexanes) to afford title compound 213 (202 mg, 85%) as awhite foam. LRMS: (calc) 420.14 (found) 421.2 (MH)+.

Step 4:N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)benzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide(214)

Using Procedure D-2 (Table 3) with compound 213 the title compound 214was obtained (100 mg, 51%) as white solid. ¹H NMR (CD₃OD) δ (ppm) 1H,8.70 (bs, 1H), 8.64 (bs, 1H), 7.62-7.85 (m, 4H), 5.20 (s, 1H), 5.10 (m,1H), 4.53 (s, 1H), 3.56-3.80 (m, 3H), 2.13 (m, 2H). LRMS (ESI): (calc.)407.1 (found) 406.3 (M)−.

Example 103N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazole-5-carboxamide(218) Step 1: (1S,4S)-tert-butyl5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(215)

Using Procedure I-2 (Table 3) with 1-iodo-3-(trifluoromethyl)benzene and(1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate thetitle compound 215 was obtained (8.88 g, 70%) as white solid. LRMS:(calc) 342.16 (found) 343.3 (MH)+.

Step 2:(1S,4S)-5-(3-(trifluoromethyl)phenyl)-5-aza-2-azoniabicyclo[2.2.1]heptanechloride (216)

Using Procedure B-2 (Table 3) with compound 215 the title compound 216was obtained (7.17 g, 100%) as yellow solid. LRMS: (calc) 242.0 (found)243.2 (MH)+.

Step 3: ethyl2-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazole-5-carboxylate(217)

A suspension of ethyl 2-bromothiazole-5-carboxylate (0.125 mL, 0.834mmol), title compound 216 (425 mg, 1.525 mmol), and triethylamine (0.465mL, 3.34 mmol) in dioxane (1.525 mL) was sonicated for 1 h. More THF (2mL) was added and the mixture was sonicated for another 2 h. The mixturewas partitioned between water and ethyl acetate and the organic layerwas washed with water (×2) then with brine. The organic extract wasdried (magnesium sulfate) and solvent evaporated. The residue waspurified via ISCO (0-50% Hex/EtOAc; 40 g silica gel column) to obtaintitle compound 217 (316 mg, 95%) as a white foam. LRMS: (calc) 397.11(found) 398.1 (MH)+.

Step 4:N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)thiazole-5-carboxamide(218)

Using Procedure D-2 (Table 3) with compound 217 the title compound 218was obtained (124 mg, 82%) as off-white solid. ¹H NMR (CD₃OD) δ (ppm):7.66 (bs, 1H), 7.33 (t, J=8 Hz, 1H), 6.82-6.91 (m, 3H), 4.76 (s, 1H),4.74 (s, 1H), 3.70 (dd, J=9.2 Hz, 18 Hz, 2H), 3.40 (d, J=9.6 Hz, 1H),3.23 (d, J=9.2 Hz, 1H), 2.19 (s, 2H). LRMS (ESI): (calc.) 384.09 (found)383.2 (M)−.

Example 104 (1S,4S)-cyclopentyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(220) Step 1: (1S,4S)-cyclopentyl5-(5-(ethoxycarbonyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(219)

To a solution of cyclopentanol (0.096 mL, 1.054 mmol) and DSC (0.225 g,0.878 mmol) in ACN (3 mL) and DCM (3 mL) at 0° C. was added 2,6-lutidine(0.102 mL, 0.878 mmol). The mixture was stirred at room temperature,overnight. To the resulting mixture was added a solution of titlecompound 212 (0.25 g, 0.878 mmol) and DIPEA (0.306 mL, 1.756 mmol) inDCM. The mixture was stirred for 1 h at room temperature then at 45° C.overnight. More of the DCS solution substituting bases for DIPEA wasmade and the mixture was matured 4 h before adding to reaction mixture.The reaction mixture was stirred at 45° C. overnight then concentratedand purified by flash chromatography: 40 g SiO2, EA/H 0% to 50% over 20min to afford title compound 219 (83 mg, 26%) as a clear oil thatsolidified upon standing. LRMS: (calc) 360.18 (found) 361.3 (MH)+. ¹HNMR (CDCl₃, 400 MHz) δ (ppm): 8.84-8.83 (m, 2H), 5.10 (m, 2H), 4.73-4.58(m, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.72-3.35 (m, 4H), 2.00-1.60 (m, 10H),1.37 (t, J=7.0 Hz, 3H).

Step 2: (1S,4S)-cyclopentyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(220)

Using Procedure D-2 (Table 3) with compound 219 the title compound 220was obtained (62 mg, 78%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.07 (s, 1H), 9.00 (s, 1H), 8.65 (s, 2H), 4.93 (m, 2H), 4.49 (d, J=8.2Hz, 1H), 3.60-3.50 (m, 1H), 3.49-3.25 (m, 2H), 3.24-3.10 (m, 1H), 1.93(d, J=10.4 Hz, 2H), 1.85-1.40 (m, 8H). LRMS (ESI): (calc.) 347.2 (found)348.3 (MH)+.

Example 105 (1S,4S)-pyridin-3-ylmethyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(222) Step 1: (1S,4S)-pyridin-3-ylmethyl5-(5-(ethoxycarbonyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(221)

To a solution of pyridin-3-ylmethanol (0.086 mL, 0.878 mmol) in THF (2.5mL) was added N,N-carbonyldiimidazole (0.142 g, 0.878 mmol). Afterstirring for 1 h a solution of TEA (0.245 mL, 1.756 mmol), DBU (0.132mL, 0.878 mmol) and the title compound 212 (0.25 g, 0.878 mmol) in THF(2.5 mL) was added. The reaction mixture was stirred overnight at 45° C.The mixture was cooled down and diluted with ethyl acetate. The organiclayer was washed with water, brine, dried over Na₂SO₄, filtered andconcentrated. The crude was purified by flash chromatography (twice): 40SiO2, MeOH/EA 0% to 20% over 20 min to afford title compound 221 (80 mg,24%) as an oil. ¹H NMR (400 MHz, CDCl3) δ (ppm): 8.81-8.77 (m, 2H),8.60-8.57 (m, 2H), 7.83-7.76 (m, 1H), 7.42-7.35 (m, 1H), 5.21-5.05 (m,1H), 5.21 (s, 2H), 4.79 (s, 1H), 4.72-4.64 (m, 1H), 4.31 (qd, J=7.1, 1.8Hz, 2H), 3.69-3.41 (m, 3H), 1.98 (d, J=8.0 Hz, 2H), 1.34 (td, J=7.1, 2.5Hz, 3H).

Step 2: (1S,4S)-pyridin-3-ylmethyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(222)

Using Procedure D-2 (Table 3) with compound 221 the title compound 222was obtained (30 mg, 39%) as a white solid. ¹H NMR (MeOD-d4) δ (ppm):8.66 (s, 2H), 8.59 and 8.52 (2s, 1H), 8.50 and 8.46 (2d, J=4.5 Hz, 1H),7.90 and 7.82 (2d, J=7.8 Hz, 1H), 7.50-7.39 (m, 1H), 5.21 (s, 1H), 5.07(s, 1H), 5.20-5.08 (m, 1H), 4.69 (d, J=9.8 Hz, 1H), 3.66-3.36 (m, 4H),2.05-1.99 (m, 2H) LRMS (ESI): (calc.) 370.1 (found) 371.2 (MH)+.

Example 1062-((1S,4S)-5-(benzo[d]isoxazol-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide(224) Step 1: ethyl2-((1S,4S)-5-(benzo[d]isoxazol-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxylate(223)

Using Procedure G-2 (Table 3) with compound 212 the title compound 223was obtained (53.6 mg, 21%) as a white solid. LRMS (ESI): (calc.) 365.15(found) 366.3 (MH)+.

Step 2:2-((1S,4S)-5-(benzo[d]isoxazol-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5-carboxamide(25)

Using Procedure D-2 (Table 1) with compound 223 the title compound 224was obtained (35.6 mg, 69%) as an off-white solid. ¹H NMR (400 MHz,CD₃OD) δ (ppm): 8.66 (s, 1H), 8.59 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.53(t, J=7.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 5.20(s, 1H), 3.99 (d, J=9.2 Hz, 1H), 3.80 (d, J=10.8 Hz, 1H), 3.68 (m, 2H),2.20 (dd, J=10 Hz, 13.6 Hz, 2H). LRMS (ESI): (calc.) 352.1 (found) 351.0(M−H).

Example 1072-fluoro-N-hydroxy-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide(227) Step 1:2-fluoro-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoicacid (225)

Using Procedure I-2 (Table 3) with compound 216 and4-bromo-2-fluorobenzoic acid the title compound 225 was obtained (250mg, 75%) as a brown paste. LRMS (ESI): (calc.) 380.11 (found) 377.3(M-3).

Step 2: methyl2-fluoro-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoate(226)

A stirring solution of title compound 225 (250 mg 0.657 mmol), 2N HCl inether (1 mL, 2.00 mmol) and methanol (25 mL) was refluxed over theweekend. The mixture was concentrated and the residue was purified bychromatography: 20 g SiO2, dry loaded on a samplet, 0% to 50% ethylacetate in hexanes over 20 minutes to afford title compound 226 (120 mg,46%) as a white foam. LRMS (ESI): (calc.) 394.13 (found) 395.3 (MH)+. ¹HNMR (CDCl₃, 400 MHz) δ (ppm): 7.77 (t, J=8.6 Hz, 1H), 7.28 (t, J=7.8 Hz,1H), 6.92 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.67 (dd, J=8.3, 2.4 Hz, 1H),6.28 (dd, J=8.9, 2.3 Hz, 1H), 6.17 (dd, J=14.1, 2.3 Hz, 1H), 4.56 (d,J=6.1 Hz, 2H), 3.84 (s, 3H), 3.69 (dd, J=8.7, 1.8 Hz, 1H) 3.63 (dd,J=9.0, 1.8 Hz, 1H), 3.30 (dd, J=9.0, 0.8 Hz, 1H), 3.22 (d, J=8.0 Hz,1H), 2.20-2.13 (m, 2H).

Step 3:2-fluoro-N-hydroxy-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide(227)

Using Procedure D-2 (Table 3) with compound 226 the title compound 227was obtained (60 mg, 47%) as a white solid. ¹H NMR (400 MHz, (DMSO-d₆) δ(ppm): 10.47 (s, 1H), 8.91 (s, 1H), 7.37 (t, J=8.6 Hz, 1H), 7.31 (t,J=7.9 Hz, 1H), 6.88-6.81 (m, 2H), 6.78 (s, 1H), 6.44 (s, 1H), 6.41 (s,1H), 4.74 (d, J=13.7 Hz, 2H), 3.63-3.53 (m, 2H), 3.04 (d, J=9.4 Hz, 1H),3.01 (d, J=9.2 Hz, 1H), 2.05 (s, 2H). LRMS (ESI): (calc.) 395.13 (found)396.3 (MH)+.

Example 108N-hydroxy-2-(7-(4-(trifluoromethyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyrimidine-5-carboxamide(234) Step 1: tert-butyl7-benzyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (29)

A solution of 1-Boc-4-piperidone (3 g, 15.06 mmol), benzylamine (1.73mL, 15.81 mmol) and acetic acid (0.86 mL, 15.06 mmol) in MeOH (20 ml)was added a stirred suspension of paraformaldehyde (1 g) in MeOH (30 ml)at reflux. The mixture was stirred for 1 h and more paraformaldehyde (1g) was added and the mixture was stirred for 4 h. The mixture was cooledand concentrated. The residue was dissolved in ether (40 mL) and 1M KOHsolution (20 mL) was added. The layers were split and the aqueousmixture was extracted with ether four times. The combined organics weredried over Na₂SO₄ for 20 min, filtered and concentrated. The yellowresidue was purified by flash chromatography: 0% to 50% EA/H over 20 minon 80 g SiO₂ to afford title compound 228 (5 g, 100%). LRMS (ESI):(calc.) 330.19 (found) 362.9 (MH+MeOH)+.

Step 2: tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(229)

To a stirring solution of title compound 228 (3.6 g, 10.90 mmol) in EtOH(100 mL) was added p-toluenesulfanhydrazine (2.435 g, 13.07 mmol) atroom temperature then the reaction mixture was heated at reflux for 2 h.The mixture was cooled to room temperature and concentrated. The residuewas dissolved in THF (60 mL) and water (15 mL) and NaBH₄ (4.12 g, 109mmol) was added portionwise at 0° C. over 5 min (effervescence). Thereaction mixture was stirred for 30 minutes at room temperature then 3 hat reflux. The mixture was cooled, water was added and the mixture wasextracted with Et₂O (4 times). The organic extracts were dried overNa₂SO₄, filtered and concentrated. Purified residue by flashchromatography: 40 g SiO₂, 0% to 50% EA/hexanes over 30 min. to affordtitle compound 229 (1.35 g, 27%). LRMS (ESI): (calc.) 316.22 (found)317.5 (MH)+.

Step 3: 3-benzyl-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (230)

Using Procedure B-2 (Table 3) with compound 229 the title compound 230was obtained (1.54 g, 100%) as light pink foam. LRMS (ESI): (calc.)216.16 (found) 217.3 (MH)+. ¹H NMR (CDCl₃) δ (ppm): 7.72-7.71 (m, 2H),7.44-7.41 (m, 3H), 4.46 (s, 2H), 3.51-3.46 (m, 4H), 2.67 (s, 4H), 2.55(m, 2H), 2.12-2.00 (m, 2H).

Step 4:3-benzyl-7-(4-(trifluoromethyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane(231)

Using Procedure I-2 (Table 3) with compound 230 the title compound 231was obtained (0.41 g, 66%). LRMS (ESI): (calc.) 361.18 (found) 362.4(MH)+. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.30 (d, J=5.1, 1H), 7.12-7.04(m, 3H), 6.88-6.86 (m, 3H), 6.76 (d, J=4.9 Hz, 1H), 4.37-4.15 (m, 2H),3.23 (s, 2H), 3.15 (dd, J=12.9, 2.3 Hz, 2H), 2.84 (d, J=10.8 Hz, 2H),2.20 (d, J=11.0 Hz, 2H), 1.99 (s, 2H), 1.78 (m, 1H), 1.64 (m, 1H).

Step 5:3-(4-(trifluoromethyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonaneformate (232)

Using Procedure H-2 (Table 3) with compound 231 the title compound 232was obtained (0.36 g, 80%) as a clear oil. LRMS (ESI): (calc.) 271.13(found) 272.3 (MH)+. ¹H NMR (CDCl₃) δ (ppm): 8.38 (d, J=5.1 Hz, 1H),8.04 (s, 3H), 7.06 (s, 1H), 6.98 (d, J=5.1 Hz, 1H), 4.40 (d, J=12.7 Hz,2H), 3.65 (d, J=13.1 Hz, 2H), 3.35 (d, J=13.1 Hz, 2H), 3.14 (d, J=12.5Hz, 2H), 2.34 (s, 2H), 2.04-1.93 (m, 1H), 1.74 (dd, J=17.5, 5.0 Hz, 1H).

Step 6: ethyl2-(7-(4-(trifluoromethyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyrimidine-5-carboxylate(233)

Using Procedure C-2 (Table 3) with compound 232 the title compound 233was obtained (0.28 g, 76%) as clear oil. LRMS (ESI): (calc.) 421.17(found) 422.6 (MH)+. ¹H NMR (CDCl₃) δ (ppm): 8.52 (s, 2H), 8.07 (d,J=5.5 Hz, 1H), 6.59 (s, 1H), 6.50 (d, J=5.3 Hz, 1H), 5.18 (d, J=14.1 Hz,2H), 4.47 (d, J=13.1 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 3.32-3.20 (m, 4H),2.18 (s, 2H), 2.11-1.97 (m, 2H), 1.32 (t, J=7.1 Hz, 3H).

Step 7:N-hydroxy-2-(7-(4-(trifluoromethyl)pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyrimidine-5-carboxamide(234)

Using Procedure D-2 (Table 3) with compound 233 the title compound 234was obtained (0.18 g, 64%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 10.82 (s, 1H), 8.88 (s, 1H), 8.36 (s, 2H), 8.01 (d, J=5.1 Hz,1H), 6.68 (s, 1H), 6.45 (d, J=5.1 Hz, 1H), 4.88 (d, J=23.3 Hz, 2H), 4.46(d, J=22.9 Hz, 2H), 3.14 (d, J=23.3 Hz, 2H), 3.05 (d, J=23.1 Hz, 2H),2.07 (s, 2H), 2.00-1.90 (m, 2H). LRMS (ESI): (calc.) 408.15 (found)409.6 (MH)+.

Example 109N-hydroxy-2-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide(244) Step 1:(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(235)

To a suspension of trans-D-hydroxyproline (3 g, 22.88 mmol) in Et₃N (6mL) and MeOH (30 mL) was added Boc anhydride (5.49 g, 25.2 mmol). Themixture was stirred at 40° C. until a clear solution was obtained. Themixture was then concentrated, diluted with 1N NaOH (20 mL), washed withhexanes, acidified with 3N HCl, salted and extracted with copiousamounts of ethyl acetate (four times). Organics were dried over Na₂SO₄and concentrated to afford title compound 235 (5.2 g, 98%) as a whitefoam. LRMS (ESI): (calc.) 1.1 (found) 230.2 (MH)−.

Step 2: (2S,4R)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (236)

To a solution of compound 235 (5.2 g, 22.49 mmol) in THF (50 mL) wasadded diazomethane (38.5 mL, 27.0 mmol, 0.7M) dropwise until yellowcolor persists. The mixture was concentrated to afford title compound236 (5.3 g, 96%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ (ppm):4.50-4.47 (m, 1H), 4.44 (t, J=7.7 Hz, 1H), 3.76-3.43 (m, 2H), 3.73 (s,3H), 2.33-2.22 (m, 1H), 2.11-2.03 (m, 1H), 1.91 (m, 1H), 1.45-1.41 (m,9H). LRMS (ESI): (calc.) 245.13 (found) 146.0 (M-Boc+H)⁺.

Step 3: (2S,4R)-tert-butyl4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (237)

To a solution of compound 236 (6.4 g, 26.09 mmol) in THF (80 mL) at 0°C. was added a solution of LiBH₄ (2.063 g, 94.76 mmol) in one shot. Thesuspension was stirred at 0° C. for 1 h then at room temperatureovernight. The mixture was cooled to 0° C. and water (52 mL) then 6N HCl(20 mL) were added. The layers were separated and the aqueous layer wasextracted with ethyl acetate (3×70 mL). The combined organics werewashed with 2N NaOH, 2N HCl and brine (20 mL each). The organic layerswere dried over Na₂SO₄ filtered and concentrated to afford titlecompound 237 (5.4 g, 95%) as clear oil. LRMS (ESI): (calc.) 217.13(found) 256.3 (M+K).

Step 4: (2S,4R)-tert-butyl4-(tosyloxy)-2-(tosyloxymethyl)pyrrolidine-1-carboxylate (238)

Using Procedure E-2 (Table 3) with compound 237 the title compound 238was obtained (6.4 g, 49%) as a white solid. LRMS (ESI): (calc.) 525.15(found) 426.4 (M-Boc+H).

Step 5: (1R,4R)-tert-butyl5-benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (239)

Using Procedure F-2 (Table 3) with compound 238 the title compound 239was obtained (0.7 g, 26%). LRMS (ESI): (calc.) 288.18 (found) 289.3(MH)+.

Step 6: (1R,4R)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane (240)

Using Procedure B-2 (Table 3) with compound 239 the title compound 240was obtained (0.59 g, 93%) as beige solid.

Step 7:(1R,4R)-2-benzyl-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane(241)

Using Procedure I-2 (Table 3) with compound 240 the title compound 241was obtained (0.32 g, 84%). LRMS (ESI): (calc.) 333.15 (found) 334.5(MH)+.

Step 8:(1R,4R)-2-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptaneformate (242)

Using Procedure H-2 (Table 3) with compound 241 the title compound 242was obtained (0.30 g, 100%) as clear oil. LRMS (ESI): (calc.) 243.10(found) 244.2 (MH)+.

Step 9: ethyl2-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxylate(243)

Using Procedure C-2 (Table 3) with compound 242 the title compound 243was obtained (0.21 g, 70%) as a white solid. LRMS (ESI): (calc.) 393.14(found) 394.5 (MH)+. ¹H NMR (CDCl₃) δ (ppm): 8.81 (d, J=5.5 Hz, 2H),8.23 (d, J=5.3 Hz, 1H), 6.73 (d, J=5.3 Hz, 1H), 6.49 (s, 1H), 5.24 (s,1H), 5.10 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.75-3.68 (m, 3H), 3.43 (d,J=9.4 Hz, 1H), 2.13 (s, 2H), 1.34 (t, J=7.1 Hz, 3H).

Step 10:N-hydroxy-2-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide(244)

Using Procedure D-2 (Table 3) with compound 243 the title compound 244was obtained (0.15 g, 71%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ (ppm): 11.06 (s, 1H), 9.00 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.27(d, J=5.2 Hz, 1H), 6.81 (d, J=5.1 Hz, 1H), 6.73 (s, 1H), 5.08 (s, 1H),5.05 (s, 1H), 3.70-3.60 (m, 2H), 3.46 (d, J=10.6 Hz, 1H), 3.40-3.30 (m,1H), 2.18-2.00 (m, 2H). LRMS (ESI): (calc.) 380.12 (found) 381.4 (MH)+.

Example 1104-((1S,4S)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxybenzamide(249) Step 1: (1S,4S)-tert-butyl5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (245)

Using Procedure I-2 (Table 3) with (1R,4R)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 3-bromobenzonitrile thetitle compound 245 was obtained (2.4 g, 79%) as an off-white paste. LRMS(ESI): (calc.) 299.16 (found) 300.3 (MH)+.

Step 2: 3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzonitrilehydrochloride (246)

Using Procedure B-2 (Table 3) with compound 245 the title compound 246was obtained (1.85 g, 98%) as a white solid. LRMS (ESI): (calc.) 199.11(found) 200.2 (MH)+.

Step 3: tert-butyl4-((1S,4S)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoate(247)

Using Procedure G-2 (Table 3) with compound 246 the title compound 247was obtained (0.45 g, 33%) as a clear oil. LRMS (ESI): (calc.) 375.19(found) 376.5 (MH)+. ¹H NMR (DMSO-d₆) δ (ppm): 7.65 (d, J=9.2 Hz, 2H),7.28 (dd, J=8.4, 7.4 Hz, 1H), 7.01 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.89(dd, J=8.4, 2.2 Hz, 1H), 6.60 (d, J=8.6 Hz, 2H), 4.75 (s, 2H), 3.59 (dt,J=10, 2.5 Hz, 2H), 3.08 (d, J=9.6 Hz, 1H), 3.02 (d, J=9.4 Hz, 1H), 2.08(s, 2H), 1.48 (s, 9H).

Step 4:4-((1S,4S)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)benzoicacid (248)

To a saturated mixture of HCl (gas) and nitromethane (25 mL) was addedtitle compound 247 (0.85 g, 2.264 mmol). The clear solution was stirred2 h then concentrated. The beige residue was triturated with etherovernight and filtered to afford title compound 248 (315 mg, 39%) as abeige solid. LRMS (ESI): (calc.) 319.13 (found) 320.3 (MH)+.

Step 5:4-((1S,4S)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-hydroxybenzamide(249)

Title compound 248 (0.21 g, 0.590 mmol) and BOP (0.287 g, 0.649 mmol)were combined and pyridine (5.90 ml) was added. The mixture was stirred15 min. Hydroxylamine hydrochloride (0.045 g, 0.649 mmol) was added andthe mixture was stirred at room temperature overnight. The mixture wasconcentrated, water and 3N HCl were added (to reach pH=5). This aqueousmixture was extracted twice with ethyl acetate. The combined organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in THF (3 mL) and MeOH (3 mL),4M KOH (0.3 ml) was added and the homogenous mixture was concentratedpartially. The resulting aq. solution was diluted with water and 3N HCl(0.4 ml) was added. The precipitate was filtered, washed with water andether and pumped on Hi-Vac overnight to afford title compound 249 (0.18g, 91%) as a pink solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.81 (s,1H), 8.70 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.27 (t, J=7.9 Hz,1H), 7.01 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.58(d, J=8.6 Hz, 2H), 4.73 (d, J=5.1 Hz, 2H), 3.57 (d, J=9.4 Hz, 2H), 3.03(t, J=10.1 Hz, 2H), 2.06 (s, 2H). LRMS (ESI): (calc.) 334.1 (found)333.4 (MH)−.

The general procedures A-2 to Q-2 used to synthesize compounds of thisinvention are described in the Table 3. A specific example of eachgeneral procedure is provided in the indicated step of a particularexample. It is realized that substrates and methods may be modifiedand/or adapted by those of skill in the art in order to facilitate thesynthesis of the compounds within the scope of the present invention.

TABLE 3 Proc Sc Ex Step Reaction Conditions A-2 30 100 1

B-2 30 100 2

C-2 30 100 3

D-2 30 100 4

E-2 31 101 1

F-2 31 101 2

F-2 39 109 5

G-2 31 101 4

G-2 36 106 1

H-2 31 101 5

I-2 31 101 6

J-2 32 102 3

K-2 34 104 1

K-2 35 105 1

L-2 37 107 2

M-2 38 108 1

N-2 38 108 2

O-2 39 109 1

P-2 39 109 3

Q-2 40 110 4

The examples described in Table 4 were prepared following thepreparative sequences (general procedures A-1 to Q-2) as indicated inTable 3 or other preparative sequence(s) from Table 1 and/or Table 5.

TABLE 4 Ex Cpd Structure Name Characterization 100 203

2-((1S,4S)-5-benzhydryl- 2,5-diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide ¹HNMR (DMSO-d₆) δ (ppm): 7.80 (dd, J =8.0, 2.0 Hz, 1H), 7.61 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.46-7.41 (m,3H), 7.38-7.30 (m, 3H), 3.62 (t, J = 7.2 Hz, 2H), 2.06 (t, J = 7.2 Hz,2H), 1.61-1.51 (m, 4H), 1.44-1.28 (m, 4H). LRMS: (calc) 390.12 (found)391.3 (MH)⁺. 101 210

N-hydroxy-4-((1R,4R)- 5-m-tolyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)benzamide (MeOH-d₄) δ (ppm): 7.55 (d, J = 8.8 Hz, 2H), 6.99 (t, J = 7.6Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.43 (d, J = 7.5 Hz, 1H), 6.42-6.35(m, 2H), 4.61 (s, 1H), 4.55 (s, 1H), 3.60 (t, J = 9.0 Hz, 2H), 3.23 (d,J = 9.0 Hz, 1H), 3.08 (d, J = 8.8 Hz, 1H), 2.22 (s, 3H), 2.18-2.03 (m,2H). MS(m/z): 324.4 (M + H). 102 214

N-hydroxy-2-((1S,4S)- 5-(3-(trifluoromethyl) benzoyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (CD₃OD) d(ppm)1H: 8.70 (bs, 1H), 8.64 (bs, 1H), 7.62-7.85 (m, 4H), 5.20 (s, 1H), 5.10(m, 1H), 4.53 (s, 1H), 3.56-3.80 (m, 3H), 2.13 (m, 2H). LRMS(ESI):(calc.) 407.1 (found) 406.3 (M)− 103 218

N-hydroxy-2-((1S,4S)- 5-(3-(trifluoromethyl)- phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)thiazole- 5-carboxamide (CD₃OD) d(ppm)1H: 7.66 (bs, 1H), 7.33 (t, J = 8 Hz, 1H), 6.82-6.91 (m, 3H), 4.76 (s,1H), 4.74 (s, 1H), 3.70 (dd, J = 9.2 Hz, 18 Hz, 2H), 3.40 (d, J = 9.6Hz, 1H), 3.23 (d, J = 9.2 Hz, 1H), 2.19 (s, 2H). LRMS(ESI): (calc.)384.0 (found) 383.2 (M)− 104 220

(1S,4S)-cyclopentyl 5-(5-(hydroxycarbamoyl) pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate ¹H NMR (DMSO-d₆) δ (ppm):11.07 (s, 1H), 9.00 (s, 1H), 8.65 (s, 2H), 4.93 (m, 2H), 4.49 (d, J =8.2 Hz, 1H), 3.60-3.50 (m, 1H), 3.49-3.25 (m, 2H), 3.24-3.10 (m, 1H),1.93 (d, J = 10.4 Hz, 2H), 1.85-1.40 (m, 8H) LRMS(ESI): (calc.) 347.2(found) 348.3 (MH)+. 105 222

(1S,4S)-pyridin-3- ylmethyl 5-(5- (hydroxycarbamoyl)pyrimidin-2-yl)-2,5- diazabicyclo[2.2.1] heptane-2-carboxylate (MeOD-d4)d(ppm) 1H: 8.66 (s, 2H), 8.59 and 8.52 (2s, 1H), 8.50 and 8.46 (2d, J =4.5 Hz, 1H), 7.90 and 7.82 (2d, J = 7.8 Hz, 1H), 7.50- 7.39 (m, 1H),5.21 (s, 1H), 5.07 (s, 1H), 5.20-5.08 (m, 1H), 4.69 (d, J = 9.8 Hz, 1H),3.66-3.36 (m, 4H), 2.05-1.99 (m, 2H) LRMS(ESI): (calc.) 370.1 (found)371.2 (MH)+ 106 224

2-((1S,4S)-5-(benzo [d]isoxazol-3-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (CD3OD) d(ppm) 1H: 8.66(s, 1H), 8.59 (s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H),7.41 (d, J = 8.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 5.20 (s, 1H), 3.99(d, J = 9.2 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H), 3.68 (m, 2H), 2.20 (dd,J = 10 Hz, 13.6 Hz, 2H) LRMS(ESI): (calc.) 352.13 (found) 351.0 (M)− 107227

2-fluoro-N-hydroxy- 4-((1S,4S)-5-(3- (trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)benzamide (DMSO-d₆) δ (ppm): 10.47(s, 1H), 8.91 (s, 1H), 7.37 (t, J = 8.6 Hz, 1H), 7.31 (t, J = 7.9 Hz,1H), 6.88- 6.81 (m, 2H), 6.78 (s, 2H), 6.44 (s, 1H), 6.41 (s, 1H), 4.74(d, J = 13.7 Hz, 2H), 3.63-3.53 (m, 2H), 3.04 (d, J = 9.4 Hz, 1H), 3.01(d, J = 9.2 Hz, 1H), 2.05 (s, 2H). MS (m/z): 396.3 (M + H). 108 234

N-hydroxy-2-(7-(4- (trifluoromethyl) pyridin-2-yl)-3,7-diazabicyclo[3.3.1] nonan-3-yl)pyrimidine- 5-carboxamide (DMSO-d₆) δ(ppm): 10.82 (s, 1H), 8.88 (s, 1H), 8.36 (s, 2H), 8.01 (d, J = 5.1 Hz,1H), 6.68 (s, 1H), 6.45 (d, J = 5.1 Hz, 1H), 4.88 (d, J = 23.3 Hz, 2H),4.46 (d, J = 22.9 Hz, 2H), 3.14 (d, J = 23.3 Hz, 2H), 3.05 (d, J = 23.1Hz, 2H), 2.07 (s, 2H), 2.00-1.90 (m, 2H). MS (m/z): 409.6 (M + H). 109244

N-hydroxy-2-((1R,4R)- 5-(4-(trifluoromethyl) pyridin-2-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (DMSO-d₆)δ (ppm): 11.06 (s, 1H), 9.00 (s, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.27(d, J = 5.2 Hz, 1H), 6.81 (d, J = 5.1 Hz, 1H), 6.73 (s, 1H), 5.08 (s,1H), 5.05 (s, 1H), 3.70-3.60 (m, 2H), 3.46 (d, J = 10.6 Hz, 1H), 3.40-3.30 (m, 1H), 2.18-2.00 (m, 2H). MS (m/z): 381.4 (M + H). 110 249

4-((1S,4S)-5-(3- cyanophenyl)- 2,5-diazabicyclo [2.2.1]heptan- 2-yl)-N-hydroxybenzamide (dmso-d6) δ (ppm) 1H: 10.81 (s, 1H), 8.70 (d, J= 1.8Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.27 (t, J = 7.9 Hz, 1H), 7.01 (s,1H), 6.95 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.58 (d, J =8.6 Hz, 2H), 4.73 (d, J = 5.1 Hz, 2H), 3.57 (d, J = 9.4 Hz, 2H), 3.03(t, J = 10.1 Hz, 2H), 2.06 (s, 2H). LRMS(ESl): (calc.) 334.1 (found)333.4 (MH)− 111 250

2-((1S,4S)-5-benzyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.03 (s, 0.9H),8.98 (s, 0.9H), 8.62 (d, J = 13.5 Hz, 2H), 7.32-7.24 (m, 4H), 7.22-7.16(m, 1H), 4.78 (s, 1H), 3.68 (s, 2H), 3.64 (d, J = 11.0 Hz, 1H), 3.56(s,1H), 3.39-3.32 (m, 1H), 2.89-2.80 (m, 1H), 2.44 (d, J = 9.4 Hz, 1H),1.92 (d, J = 10.4 Hz, 1H), 1.77 (d, J = 9.4 Hz, 1H). LRMS: (calc.)325.15 (found) 326.4 (MH)⁺. 112 251

N-hydroxy-2-((1S,4S)- 5-p-tolyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrimidine- 5-carboxamide (DMSO-d6) δ (ppm): 11.0 (br s,0.5H), 9.0 (br s, 0.4H), 8.62 (s, 1H), 8.56 (s, 1H), 6.92 (d, J = 8.2Hz, 2H), 6.48 (d, J = 8.4 Hz, 2H), 4.97 (s, 1H), 4.56 (s, 1H), 3.55-3.51(m, 1H), 3.51-3.45 (m, 2H), 2.90 (d, J = 8.8 Hz, 1H), 2.12 (s, 3H), 2.03(m, 2H). LRMS: (calc.) 325.2 (found) 324.3 (MH)⁺. 113 252

2-((1S,4S)-5-(4- chlorophenyl)-2,5- diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.03 (s, 1H), 8.99(s, 1H), 8.63 (s, 1H), 8.58 (s, 1H), 7.12 (dd, J = 7.0, 2.2 Hz, 2H),6.60 (dd, J = 8.1, 3.3 Hz, 2H), 5.00 (s, 1H), 4.62 (s, 1H), 3.62 (dd, J= 9.0, 1.7 Hz, 1H), 3.55 (dd, J = 10.8, 1.6 Hz, 1H), 3.46 (d, J = 10.6Hz, 1H), 2.95 (d, J = 9.0 Hz, 1H), 2.05 (s, 2H). LRMS(ESI): (calc.)345.1 (found) 346.1 (MH)+ 114 253

(1S,4S)-tert-butyl 5- (5-(hydroxycarbamoyl) pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (DMSO-d6) δ (ppm): 11.09 (s,1H), 9.03 (s, 1H), 8.64 (s, 2H), 4.91 (s, 1H), 4.45 (d, J = 11.7 Hz,1H), 3.60- 3.30 (m, 3H), 3.14 (d, J = 9.7 Hz, 1H), 1.93 (s, 1H), 1.90(s, 1H), 1.38 (s, 5H), 1.33 (s, 4H). LRMS(ESI): (calc.) 335.16 (found)336.3 (MH)+ 115 254

2-((1S,4S)-5-(3- fluorophenyl)-2,5- diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.03 (s, 1H), 8.98(s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.20-7.07 (m, 1H), 6.45-6.31 (m,3H), 5.01 (s, 1H), 4.65 (s, 1H), 3.63-3.61 (m, 1H), 3.58-3.54 (m, 1H),3.7 (d, J = 10.8 Hz, 1H), 2.99 (d, J = 9.2 Hz, 1H), 2.05 (s, 2H).LRMS(ESI): (calc.) 329.13 (found) 330.2 (MH)+ 116 255

2-((1S,4S)-5-(4- fluorophenyl)-2,5- diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.02 (s, 1H), 8.98(s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 6.96 (t, J = 8.9 Hz, 2H), 6.62-6.55 (m, 2H), 4.99 (s, 1H), 4.59 (s, 1H), 3.63 (dd, J = 8.8, 1.6 Hz,1H), 3.56-3.53 (m, 1H), 3.47 (d, J = 10.5 Hz, 1H), 2.92 (d, J = 9.0 Hz,IH), 2.05 (s, 2H). LRMS(ESI): (calc.) 329.1 (found) 330.2 (MH)+ 117 256

2-((1S,4S)-2,5- diazabicyclo[2.2.1] heptan-2-yl)-N- hydroxypyrimidine-5-carboxamide (DMSO-d6) δ (ppm): 11.17 (br s, 0.5H), 9.79 (s, 1H), 9.19(s, 1H), 8.71 (s, 2H), 5.00 (s, 1H), 4.64 (s, 1H), 3.79 (d, J = 11.7 Hz,1H), 3.58 (d, J = 11.5 Hz, 1H), 3.38-3.22 (m, 1H), 3.20-3.10 (m, 1H),2.11 (d, J = 10.6 Hz, 1H), 1.93 (d, J = 10.8 Hz, 1H) LRMS(ESI): (calc.)235.1 (found) 236.1 (MH)+ 118 257

N-hydroxy-2-((1S,4S)- 5-o-tolyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrimidine- 5-carboxamide (DMS0-d6) δ (ppm): 11.02 (s, 1H),8.97 (s, 1H), 8.61 (d, J = 4.7 Hz, 2H), 7.05-6.98 (m, 2H), 6.82 (d, J =8.3 Hz, 1H), 6.71 (t, J = 7.3 Hz, 1H), 4.96 (s, 1H), 4.34 (s, 1H), 3.73(d, J = 10.9 Hz, 1H), 3.67-3.61 (m, 1H), 3.60-3.54 (m, 1H), 3.03 (d, J =9.0 Hz, 1H), 2.16 (s, 3H), 2.06-1.96 (m, 2H). LRMS(ESI): (calc.) 326.15(found) 326.3 (MH)+ 119 258

2-((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan- 5-yl)-N-hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.06 (s, 1H), 8.99(s, 1H), 8.64 (s, 2H), 4.98 (s, 1H), 4.67 (s, 1H), 3.80-3.76 (d, 1H),3.63 (d, J = 7.2 Hz, 1H), 3.51-3.46 (m, 1H), 3.39 (d, J = 11.4 Hz, 1H),1.92 (d, J = 9.8 Hz, 1H), 1.86 (d, J = 10.0 Hz, 1H). LRMS(ESI): (calc.)236.1 (found) 237.1 (MH)+ 120 259

N-hydroxy-2-((1S,4S)- 5-phenyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrimidine- 5-carboxamide (DMSO-d6) δ (ppm): 11.01 (s, 1H),8.97 (s, 1H), 8.63 (s, 1H), 8.57 (s, 1H), 7.12 (t, J = 7.9 Hz, 2H),6.62- 6.54 (m, 3H), 5.00 (s, 1H), 4.62 (s, 1H), 3.63 (dd, J = 8.9, 1.5Hz, 1H), 3.58-3.53 (m, 1H), 3.49 (d, J = 10.5 Hz, 1H), 2.97 (d, J = 9.0Hz, 1H), 2.05 (s, 2H). LRMS(ESI): (calc.) 311.14 (found) 312.3 (MH)+ 121260

2-((1S,4S)-5-benzoyl- 2,5-diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide (MeOD-d4) δ (ppm): 8.69-8.62 (m, 2H),7.52-7.40 (m, 5H), 5.17 (s, 0.5H), 5.05 (s, 0.5H), 4.57 (s, 0.5H),3.79-3.74 (m, 3H), 3.64 (d, J = 10.8 Hz, 0.5H) 3.55 (d, J = 11.35 Hz,0.5H), 3.35-3.30 (m, 0.5H), 2.15- 2.04 (m, 2H) LRMS(ESI): (calc.) 339.1(found) 338.3 (M−) 122 261

N-hydroxy-2-((1S,4S)- 5-(3-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl) pyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.0(bs, 1H), 8.98 (bs, 1H), 8.63 (s, 1H), 8.58 (s, 1H), 7.31 (t, J = 8 Hz,1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.81 (s, 1H), 5.03 (s, 1H), 4.76 (s,1H), 3.69 (d, J = 1.2 Hz, 1H), 3.60 (d, J = 10.8 Hz, 1H), 3.45 (d, J =10.8 Hz, 1H), 3.03 (d, J = 9.2 Hz, 1H), 2.07 (s, 2H). LRMS(ESI): (calc.)379.1 (found) 378.2 (M)− 123 262

2-((1S,4S)-5-(2-fluoro- 4-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine- 5-carboxamide (DMSO-d6) δ(ppm): 11.0 (bs, 1H), 8.98 (bs, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 7.42(d, J = 14 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.92 (t, J = 8.8 Hz, 1H),5.00 (s, 1H), 4.72 (s, 1H), 3.84 (d, J = 8 Hz, 1H), 3.60 (s, 2H), 3.20(m, 2H), 2.06 (s, 2H). LRMS (ESI): (calc.) 397.1 (found) 396.2 (M)− 124263

N-hydroxy-2-((1S,4S)- 5-(2-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl) pyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.0(bs, 1H), 8.97 (bs, 1H), 8.62 (s, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.44(t, J = 7.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H),5.00 (s, 1H), 4.48 (s, 1H), 3.71 (m, 2H), 3.61 (m, 1H), 3.07 (d, J = 9.2Hz, 1H), 2.05 (s, 2H). LRMS(ESI): (calc.) 379.1 (found) 378.1 (M)− 125264

N-hydroxy-2-((1S,4S)- 5-(4-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl) pyrimidine-5- carboxamide (DMS0-d6) δ (ppm): 11.0(bs, 1H), 8.98 (bs, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.42 (d, J = 8.4Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 5.04 (s, 1H), 4.75 (s, 1H), 3.66 (d,J = 8.8 Hz, 1H), 3.59 (d, J = 10 Hz, 1H), 3.46 (d, J = 10 Hz, 1H), 3.08(d, J = 9.2 Hz, 1H), 2.06 (s, 2H). LRMS(ESI): (calc.) 379.1 (found)378.1 (M)− 126 265

2-((1S,4S)-5-(benzo [c][1,2,5]oxadiazol-5- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (DMSO-d6) δ(ppm): 11.0 (bs, 1H), 8.98 (bs, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 7.82(d, J = 9.6 Hz, 1H), 7.44 (bs, 1H), 6.46 (bs, 1H), 5.08 (s, 1H), 4.94(bs, 1H), 3.73- 3.54 (m, 2H), 2.11 (m, 2H). LRMS (ESI): (calc.) 353.1(found) 352.2 (M)− 127 266

2-((1S,4S)-5-(benzo [c][1,2,5]thiadiazol-5- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (DMSO-d6) δ(ppm): 11.0 (bs, 1H), 8.98 (bs, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 7.82(d, J = 9.6 Hz, 1H), 7.44 (bs, 1H), 6.82 (s, 1H), 5.08 (s, 1H), 4.91 (s,1H), 3.76 (d, J = 8 Hz, 1H), 3.65 (d, J = 10.8 Hz, 1H), 3.55 (d, J =10.8 Hz, 1H), 3.23 (d, J = 8 Hz, 1H), 2.12 (s, 2H). LRMS(ESI): (calc.)369.1 (found) 368.2 (M)− 128 267

2-((1S,4S)-5-(benzo[d] [1,3]dioxol-5-yl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm): 11.0(bs, 1H), 8.9 (bs, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 6.69 (d, J = 8.4 Hz,1H), 6.36 (d, J = 2.4 Hz, 1H), 5.96 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 5.83(d, J = 5.6 Hz, 2H), 4.95 (s, 1H), 4.52 (s, 1H) 3.59 (d, J = 8.8 Hz,1H), 3.50 (s, 2H), 2.88 (d, J = 8.8 Hz, 1H), 2.02 (s, 2H). LRMS(ESI):(calc.) 355.1 (found) 353.9 (M)− 129 268

2-((1S,4S)-5-(cyclo- hexanecarbonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (MeOD-d4) δ (ppm): 8.67(s, 2H), 5.12 (d, J = 18.0 Hz, 1H), 3.72 (d, J = 10.2 Hz, 1H), 3.63 (dd,J = 10.8, 1.9 Hz, 0.5H), 3.58- 3.48 (m, 2H), 3.37 (d, J = 11.3 Hz,0.5H), 2.64-2.58 (m, 0.5H), 2.33- 2.30 (m, 0.5H), 2.12-1.97 (m, 2H),1.82-1.66 (m, 5H), 1.57-1.19 (m, 6H). LRMS(ESI): (calc.) 345.2 (found)344.3 (M−) 130 269

2-((1S,4S)-5-(2,2- diphenylacetyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (DMSO-d6) δ (ppm):11.00 (s, 1H), 9.02 (m, 1H), 8.62 (s, 1H), 8.59 (s, 0.5H), 8.51 (s,0.5H), 7.34-7.14 (m, 7H), 7.13-7.06 (m, 2.5H), 7.02-6.97 (m, 0.5H), 5.51(s, 0.5H), 5.06 (s, 0.5H), 4.93 (d, J = 8.1 Hz, 1H), 4.82 (d, J = 7.5Hz, 1H), 3.60-3.10 (m, 4H), 1.95 and 1.85 (AB d, J = 10.0 Hz, 2H).LRMS(ESI): (calc.) 429.2 (found) 430.3 (MH)+ 131 270

N-hydroxy-4-((1S,4S)- 5-p-tolyl-2,5-diaza- bicyclo[2.2.1]heptan-2-yl)benzamide (DMSO-d6) δ (ppm): 10.79 (s, 1H), 8.70 (s, 1H), 7.53 (d ,J = 8.8 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.54 (d, J = 8.6 Hz, 2H),6.45 (d, J = 8.4 Hz, 2H), 4.64 (s, 1H), 4.54 (s, 1H), 3.54 (t, J = 7.9Hz, 2H), 3.04 (d, J = 9.2 Hz, 1H), 2.89 (d, J = 8.8 Hz, 1H), 2.12 (s,3H), 2.07-1.99 (m, 2H). LRMS(ESI): (calc.) 323.2 (found) 324.3 (MH)+ 132271

(1S,4S)-benzyl 5-(5- (hydroxycarbamoyl) pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (dmso-d6) d(ppm) 1H: 11.10 (s,1H), 8.99 (s, 1H), 8.65 (s, 2H), 7.39-7.22 (m, 5H), 5.10-5.00 (m, 2H),4.94 (s, 1H), 4.57 (d, J = 10.7 Hz, 1H), 3.60-3.30 (m, 4H), 2.0-1.80 (m,2H) LRMS(ESI): (calc.) 369.1 (found) 370.3 (MH)+ 133 272

(1S,4S)-isobutyl 5-(5- (hydroxycarbamoyl) pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (dmso-d6) d(ppm) 1H: 11.07 (s,1H), 9.01 (s, 1H), 8.65 (s, 2H), 5.00-4.90 (m, 1H), 4.53 (s, 1H),3.82-3.70 (s, 2H), 3.56 (t, J = 11.0 Hz, 1H), 3.50-3.39 (m, 2H),3.50-3.30 (m, 1H), 1.96 (s, 1H), 1.93 (s, 1H), 1.91-1.70 (m, 1H), 0.88(d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H) LRMS(ESI): (calc.) 335.2(found) 336.3 (MH)+ 134 273

N-hydroxy-2-((1S,4S)- 5-(3-(trifluoromethoxy) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl) pyrimidine-5- carboxamide (CD3OD) d(ppm) 1H: 8.65(s, 1H), 8.59 (s, 1H), 7.20 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz,1H), 6.51 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 5.14 (s, 1H), 4.64 (s, 1H),3.63-3.70 (m, 3H), 3.12 (d, J = 8.8 Hz, 1H), 2.14 (dd, J = 10 Hz, 13.2Hz, 2H) LRMS (ESI): (calc.) 395.12 (found) 394.17 (M)− 135 274

2-((1S,4S)-5-(2,2- difluorobenzo[d][1,3] dioxol-5-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide(CD3OD) d(ppm) 1H: 8.65 (s, 1H), 8.59 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H),6.55 (s, 1H), 6.30 (d, J = 8.8 Hz, 1H), 5.13 (s, 1H), 4.59 (s, 1H), 3.70(d, J = 9.2 Hz, 1H), 3.63 (s, 2H), 3.07 (d, J = 8.8 Hz, 1H), 2.14 (dd, J= 9.2 Hz, 17.2 Hz, 2H) LRMS(ESI): (calc.) 391.1 (found) 390.1 (M)− 136275

N-hydroxy-2-((1S,4S)-5- (3-(trifluoromethylthio)phenyl)-2,5-diazabicyclo [2.2.1]heptan-2-yl) pyrimidine-5- carboxamide(CD3OD) d(ppm) 1H: 8.65 (s, 1H), 8.58 (s, 1H), 7.24 (t, J = 7.6 Hz, 1H),6.91 (d, J = 7.6 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 5.15(s, 1H), 4.67 (s, 1H), 3.60-3.72 (m, 3H), 3.13 (d, J = 8.8 Hz, 1H), 2.14(dd, J = 10 Hz, 13.2 Hz, 2H) LRMS(ESI): (calc.) 411.1 (found) 410.2 (M)−137 276

N-hydroxy-2-((1S,4S)-5- (4-(trifluoromethyl) pyridin-2-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (CD3OD) d(ppm)1H: 8.66 (s, 1H), 8.61 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 6.78 (d, J =5.2 Hz, 1H), 6.73 (s, 1H), 5.20 (s, 1H), 5.05 (s, 1H), 3.72 (d, J = 11.2Hz, 2H), 3.60 (d, J = 10.8 Hz, 1H), 3.41 (d, J = 9.6 Hz, 1H), 2.15 (s,2H) LRMS (ESI): (calc.) 380.1 (found) 379.2 (M)− 138 277

N-hydroxy-2-((1S,4S)-5- (2-(trifluoromethyl) quinolin-4-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (CD3OD) d(ppm)1H: 8.63 (bs, 2H), 8.23 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H),7.70 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 6.96 (s, 1H), 5.23(s, 1H), 5.04 (s, 1H), 4.42 (d, J = 9.2 Hz, 1H), 3.98 (d, J = 10.8 Hz,1H), 3.85 (d, J = 10.8 Hz, 1H), 3.65 (d, J = 9.2 Hz, 1H), 2.28 (dd, J =10 Hz, 22 Hz, 2H) LRMS(ESI): (calc.) 430.14 (found) 429.15 (M)− 139 278

2-((1S,4S)-5-(3- (difluoromethoxy) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (CD3OD) d(ppm)1H: 8.65 (s, 1H), 8.58 (s, 1H), 7.14 (t, J = 8 Hz, 1H), 6.73 (t, J =74.5 Hz, 1H), 6.47 (d, J = 6.4 Hz, 1H), 6.38 (d, J = 6.4 Hz, 1H), 6.33(s, 1H), 5.13 (s, 1H), 4.62 (s, 1H), 3.69 (d, J = 8.8 Hz, 1H), 3.63 (s,2H), 3.12 (d, J = 8.8 Hz, 1H), 2.12 (dd, J = 10 Hz, 14 Hz, 2H)LRMS(ESI): (calc.) 377.13 (found) 376.24 (M)− 140 279

N-hydroxy-2-((1S,4S)- 5-(6-(trifluoromethyl) pyridin-2-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (CD3OD) d(ppm)1H: 8.66 (s, 1H), 8.60 (s, 1H), 7.62 (t, J = 8.2 Hz, 1H), 6.92 (d, J =7.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 5.18 (s, 1H), 5.05 (s, 1H), 3.69(m, 2H), 3.60 (d, J = 10.8 Hz, 1H), 3.40 (d, J = 9.6 Hz, 1H), 2.13 (s,2H) LRMS(ESI): (calc.) 380.12 (found) 379.24 (M)− 141 280

2-((1S,4S)-5-(benzo [c][1,2,5]oxadiazol-4- yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N-hydroxypyrimidine- 5-carboxamide (CD3OD) d(ppm)1H: 8.67 (s, 1H), 8.59 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.98 (d, J =8.8 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.45 (s, 1H), 5.23 (s, 1H), 3.95(d, J = 8.8 Hz, 1H), 3.74 (dd, J = 10.8 Hz, 23 Hz, 2H), 3.51 (d, J = 10Hz, 1H), 2.23 (q, J = 11.2 Hz, 2H) LRMS(ESI): (calc.) 353.1 (found)352.0 (M)− 142 281

N-hydroxy-2-((1S,4S)- 5-(5-(trifluoromethyl) pyridin-3-yl)-2,5-diazabicycIo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (CD3OD) d(ppm)1H: 8.66 (s, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.26 (s,1H), 5.21 (s, 1H), 4.83 (s, 1H), 3.76 (m, 2H), 3.60 (d, J = 10.8 Hz,1H), 3.25 (d, J = 9.2 Hz, 1H), 2.18 (s, 2H) LRMS(ESI): (calc.) 380.1(found) 379.0 (M)− 143 282

N-hydroxy-2-((1R,4R)- 5-p-tolyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrimidine- 5-carboxamide (dmso-d6) d(ppm) 1H: 11.02 (s,1H), 9.00 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 6.94 (d, J = 8.0 Hz, 2H),6.49 (d, J = 8.2 Hz, 2H), 4.97 (s, 1H), 4.56 (s, 1H), 3.61 (d, J = 8.6Hz, 1H), 3.53 and 3.48 (ab d, J = 10.7 Hz, 2H), 2.90 (d, J = 9.0 Hz,1H), 2.13 (s, 3H), 2.10-2.00 (m, 2H) LRMS(ESI): (calc.) 325.2 (found)326.2 (MH)+ 144 283

(1S,4S)-isopropyl 5- (5-(hydroxycarbamoyl) pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (dmso-d6) d(ppm) 1H: 11.06 (s,1H), 9.00 (s, 1H), 8.65 (s, 2H), 4.93 (d, J = 5.2 Hz, 1H), 4.80-4.68 (m,1H), 4.50 (d, J = 14.3 Hz, 1H), 3.60- 3.50 (m, 1H), 3.45-3.38 (m, 2H),3.22-3.15 (m, 1H), 1.95 (s, 1H), 1.92 (s, 1H), 1.22-1.08 (m, 6H)LRMS(ESI): (calc.) 321.1 (found) 322.2 (MH)+ 145 284

(1S,4S)-cyclopropyl- methyl 5-(5- (hydroxycarbamoyl)pyrimidin-2-yl)-2,5- diazabicyclo[2.2.1] heptane-2-carboxylate (dmso-d6)d(ppm) 1H: 11.07 (s, 1H), 9.01 (s, 1H), 8.66 (s, 2H), 4.95 (d, J = 5.1Hz, 1H), 4.53 (s, 1H), 3.90-3.70 (m, 2H), 3.56 (t, J = 9.5 Hz, 1H),3.50-3.40 (m, 2H), 3.21 (t, J = 10.5 Hz, 1H), 1.97 (s, 1H), 1.94 (s,1H), 1.15-0.95 (m, 1H), 0.55-0.49 (m, 2H), 0.48-0.46 (m, 2H) LRMS(ESI):(calc.) 333.1 (found) 334.2 (MH)+ 146 285

(1S,4S)-tetrahydro-2H- pyran-4-yl 5-(5- (hydroxycarbamoyl)pyrimidin-2-yl)-2,5- diazabicyclo[2.2.1] heptane-2-carboxylate (dmso-d6)d(ppm) 1H: 11.07 (s, 1H), 9.01 (s, 1H), 8.65 (s, 2H), 4.94 (d, J = 7.4Hz, 1H), 4.78-4.65 (m, 1H), 4.54 (d, J = 8.6 Hz, 1H), 3.82-363 (m, 2H),3.56 (t, J = 10.4 Hz, 1H), 3.50- 3.35 (m, 4H), 3.26-3.15 (m, 1H), 1.95(d, J = 12.8 Hz, 2H), 1.90-1.70 (m, 2H), 1.60-1.40 (m, 2H) LRMS(ESI):(calc.) 363.2 (found) 364.2(MH)+ 147 286

2-((1S,4S)-5-(3,5- bis(trifluoromethyl) phenyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine- 5-carboxamide (CD3OD) d(ppm) 1H: 8.66(s, 1H), 8.60 (s, 1H), 7.06 (m, 3H), 5.20 (s, 1H), 4.82 (s, 1H), 3.75(m, 2H), 3.60 (d, J = 10.8 Hz, 1H), 3.21 (d, J = 9.2 Hz, 1H), 2.17 (m,2H) LRMS(ESI): (calc.) 447.11 (found) 446.45 (M)− 148 287

2-((1S,4S)-5-(3- (dimethylcarbamoyl) phenyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide (CD3OD) d(ppm) 1H: 8.64(s, 1H), 8.57 (s, 1H), 7.22 (t, J = 8 Hz, 1H), 6.64 (m, 3H), 5.12 (s,1H), 4.65 (s, 1H), 3.70 (d, J = 8.4 Hz, 1H), 3.63 (s, 2H), 3.12 (d, J =8.8 Hz, 1H), 3.06 (s, 3H), 2.96 (s, 3H), 2.13 (m, 2H). MS (m/z): 381.0(M − H). 149 288

2-((1S,4S)-5-(3- ((dimethylamino) methyl)phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)-N- hydroxypyrimidine-5- carboxamide(CD3OD) d(ppm) 1H: 8.64 (s, 1H), 8.57 (s, 1H), 7.24 (t, J = 8 Hz, 1H),6.72 (m, 3H), 5.13 (s, 1H), 4.65 (s, 1H), 4.15 (s, 2H), 3.70 (d, J = 8.4Hz, 1H), 3.63 (s, 2H), 3.12 (d, J = 8.8 Hz, 1H), 2.72 (s, 6H), 2.13 (m,2H). MS (m/z): 369.5 (M + H) 150 289

N-hydroxy-2-((1S,4S)- 5-(3-methoxyphenyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl) pyrimidine-5- carboxamide (CD3OD) d(ppm) 1H: 8.64(s, 1H), 8.57 (s, 1H), 7.04 (t, J = 8.4 Hz, 1H- artifact from sovent),6.22 (m, 2H), 6.13 (s, 1H), 5.10 (s, 1H), 4.59 (s, 1H), 3.72 (s, 3H),3.66 (m, 3H), 3.09 (d, J = 8.8 Hz, 2H), 2.12 (dd, J = 9.6 Hz, 18.4 Hz,2H). LRMS (ESI): (calc.) 341.15 (found) 340.28 (M)− 151 290

N-hydroxy-2-((1S,4S)- 5-m-tolyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)pyrimidine-5- carboxamide (CD3OD) d(ppm) 1H: 8.64 (s, 1H), 8.57 (s, 1H),7.02 (t, J = 7.6 Hz, 1H-artifact from solvent), 6.42 (m, 3H), 5.10 (s,1H), 4.59 (s, 1H), 3.66 (m, 3H), 3.09 (d, J = 8.8 Hz, 2H), 2.24 (s, 3H),2.12 (dd, J = 9.6 Hz, 27.2 Hz, 2H). MS (m/z): 324.3 (M − H) 152 291

N-hydroxy-6-((1S,4S)- 5-p-tolyl-2,5- diazabicyclo[2.2.1] heptan-2-yl)nicotinamide (DMSO-d₆) δ (ppm): 10.87 (s, 1H), 8.82 (s, 1H), 8.40 (s,1H), 7.75 (dd, J = 9.0, 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 6.47 (d,J = 8.5 Hz, 2H), 4.90 (s, 1H), 4.56 (s, 1H), 3.58 (d, J = 7.6 Hz, 1H),3.49 (d, J = 8.6 Hz, 1H), 3.4-3.2 (m, 1H), 2.88 (d, J = 9.0 Hz, 1H),2.12 (s, 3H), 2.10-2.00 (m, 2H). MS (m/z): 323.4 (M − H) 153 292

N-hydroxy-5-((1S,4S)- 5-(3-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrazine- 2-carboxamide (DMSO-d₆) δ(ppm): 10.99 (s, 1H), 8.87 (s, 1H), 8.48 (s, 1H), 7.94 (s, 1H), 7.32 (t,J = 7.9 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.82 (s, 1H), 5.10 (s, 1H),4.83 (s, 1H), 3.70- 3.59 (m, 2H), 3.44 (d, J = 10.2 Hz, 1H), 3.08 (d, J= 9.2 Hz, 1H), 2.13-2.02 (m, 2H). MS (m/z): 380.3 (M + H) 154 293

N-hydroxy-2-((1S,4S)- 5-(pyrrolidine-1- carbonyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (DMSO-d₆) δ(ppm): 11.06 (s, 1H), 8.99 (s, 1H), 8.64 (s, 2H), 4.91 (s, 1H), 4.40 (s,1H), 3.67 (d, J = 10.5 Hz, 1H), 3.57-3.47 (m, 2H), 3.30-3.19 (m, 2H),3.17-3.09 (m, 3H), 1.87 (q, J = 9.7 Hz, 2H), 1.80- 1.59 (m, 4H). MS(m/z): 333.4 (M + H). 155 294

N-hydroxy-2-((1S,4S)- 5-(4-(trifluoromethyl) pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl) pyrimidine-5- carboxamide (CD3OD)d(ppm) 1H: 8.87 (s, 1H), 8.62 (s, 1H), 8.54 (s, 1H), 6.90 (d, J = 5.2Hz, 1H), 5.19 (s, 1H), 5.16 (s, 1H), 3.72 (m, 2H), 3.60 (m, 2H), 2.15(s, 2H). MS (m/z): 380.35 (M − H). 156 295

N-hydroxy-6-((1S,4S)- 5-(3-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl) pyridazine-3- carboxamide (DMSO-d₆) δ (ppm): 11.34(s, 1H), 8.98 (s, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.32 (t, J = 7.9 Hz,1H), 7.04 (br s, 1H), 6.87 (d, J = 6.4 Hz, 2H), 6.82 (s, 1H), 5.10 (brs, 1H), 4.83 (s, 1H), 3.72-3.60 (m, 2H), 3.44 (br s, 1H), 3.07 (d, J =9.2 Hz, 1H), 2.15-2.05 (m, 2H). MS (m/z): 380.4 (M + H). 157 296

N-hydroxy-2-((1R,4R)- 5-m-tolyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyrimidine- 5-carboxamide (DMSO-d₆) δ (ppm): 11.01 (s, 1H),8.98 (s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 7.02-6.90 (m, 1H), 6.43-6.35(m, 3H), 4.98 (s, 1H), 4.59 (s, 1H), 3.62 (dd, J = 8.9 and 1.6 Hz, 1H),3.60-3.44(m, 2H), 2.94 (d, J = 9.0 Hz, 1H), 2.18 (s, 3H), 2.04 (s, 2H).MS (m/z): 326.4 (M + H). 158 297

(CD3OD) δ (ppm): 8.66 (s, 1H), 8.59 (s, 1H), 7.31 (t, J = 8 Hz, 1H),7.03 (d, J = 8 Hz, 1H), 6.94 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.16 (s,1H), 4.70 (s, 1H), 3.73 (d, J = 8.8 Hz, 1H), 3.66 (q, J = 10.8 Hz, 2H),3.14 (d, J = 8.8 Hz, 1H), 2.17 (q, J = 10 Hz, 2H). MS (m/z): 436.4 (M −H) 159 298

2-((1S,4S)-5-(3- cyanophenyl)-2,5- diazabicyclo[2.2.1] heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide (DMSO-d₆) δ (ppm): 11.04 (s, 1H), 9.00(s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.04 (s,1H), 6.97 (d, J = 7.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.04 (s, 1H),4.74 (s, 1H), 3.64 (d, J = 6.8 Hz, 1H), 3.57 (d, J = 9.6 Hz, 1H), 3.45(d, J = 11.0 Hz, 1H), 3.04 (d, J = 9.2 Hz, 1H), 2.10-2.00 (m, 2H). MS(m/z): 337.4 (M + H). 160 299

N-hydroxy-4-((1S,4S)- 5-(3-methoxyphenyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide (DMSO-d₆) δ (ppm): 11.19 (s, 1H), 10.79 (s, 1H),7.54 (d, J = 8.6 Hz, 2H), 6.98 (t, J = 8.1 Hz, 1H), 6.55 (d, J = 8.6 Hz,2H), 6.18-6.11 (m, 2H), 6.08-6.04 (m, 1H), 4.65 (s, 1H), 4.58 (s, 1H),3.65 (s, 3H), 3.54 (d, J = 8.2 Hz, 2H), 3.06 (d, J = 9.2 Hz, 1H), 2.95(d, J = 9.0 Hz, 1H), 2.07-1.98 (m, 2H). MS (m/z): 340.5 (M + H). 161 300

N-hydroxy-4-((1S,4S)- 5-m-tolyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)benzamide (DMSO-d₆) δ (ppm): 10.79 (s, 1H), 8.70 (s, 1H),7.54 (d, J = 8.6 Hz, 2H), 6.98 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 8.6 Hz,2H), 6.41-6.33 (m, 3H), 4.65 (s, 1H), 4.57 (s, 1H), 3.55 (d, J = 8.8 Hz,2H), 3.05 (d, J = 9.0 Hz, 1H), 2.93 (d, J = 8.8 Hz, 1H), 2.17 (s, 3H),2.07-1.98 (m, 2H). MS (m/z): 324.4 (M + H). 162 301

N-hydroxy-4-((1S,4S)- 5-(3-(trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)benzamide (DMSO-d₆) δ (ppm): 10.80 (s,1H), 8.70 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H),6.84 (d, J = 7.0 Hz, 2H), 6.78 (s, 1H), 6.58 (d, J = 8.6 Hz, 2H), 4.75(s, 1H), 4.72 (s, 1H), 3.60 (t, J = 7.9 Hz, 2H), 3.03 (d, J = 9.5 Hz,2H), 2.06 (s, 2H). MS (m/z): 378.5 (M + H). 163 302

N-hydroxy-4-((1R,4R)- 5-(4-(trifluoromethyl) pyridin-2-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)benzamide (DMSO-d₆) δ (ppm): 10.83 (s,1H), 8.73 (s, 1H), 8.24 (d, J = 5.3 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H),6.78 (d, J = 5.0 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 5.02 (s, 1H), 4.75(s, 1H), 3.63 (d, J = 7.8 Hz, 1H), 3.59 (d, J = 9.0 Hz, 1H), 3.40-3.30(m, 1H), 3.05 (d, J = 9.2 Hz, 1H), 2.06 (s, 2H). MS (m/z): 379.5 (M +H). 164 303

N-hydroxy-4-((1S,4S)- 5-(4-(trifluoromethyl) pyridin-2-yl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)benzamide (dmso-d6) δ (ppm) 1H: 10.83(s, 1H), 8.73 (s, 1H), 8.24 (d, J = 5.3 Hz, 1H), 7.57 (d, J = 8.8 Hz,2H), 6.78 (d, J = 5.0 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 5.02 (s, 1H),4.75 (s, 1H), 3.63 (d, J = 7.8 Hz, 1H), 3.59 (d, J = 9.0 Hz, 1H),3.40-3.30 (m, 1H), 3.05 (d, J = 9.2 Hz, 1H), 2.06 (s, 2H). LRMS(ESI):(calc.) 378.13 (found) 379.1 (MH)+ 165 304

N-hydroxy-4-((1S,4S)- 5-(4-(trifluoromethyl) pyrimidin-2-yl)-2,5diazabicyclo[2.2.1] heptan-2-yl)benzamide ¹H NMR (DMSO-d₆) δ (ppm):10.83 (s, 1H), 8.71 (s, 1H), 8.63 (dd, J = 25.5, 4.3 Hz, 1H), 7.59 (d, J= 8.8 Hz, 2H), 6.99 (d, J = 4.9 Hz, 1H), 6.63 (d, J = 8.6 Hz, 2H), 5.05(s, 0.5H), 4.97 (s, 0.5H), 4.74 (s, 1H), 3.68 (d, J = 9.0 Hz, 1H), 3.59(t, J = 8.4 Hz, 1H), 3.52-3.35 (m, 1H), 3.15-3.05 (m, 1H), 2.15-2.05 (m,2H). 166 305

N-hydroxy-N-methyl- 4-((1S,4S)-5-p-tolyl- 2,5-diazabicyclo[2.2.1]heptan-2-yl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.77 (s, 1H), 7.53 (d, J= 8.8 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 6.52 (d, J = 8.6 Hz, 2H), 6.47(d, J = 8.4 Hz, 2H), 4.64 (s, 1H), 4.55 (s, 1H), 3.55 (t, J = 7.6 Hz,2H), 3.18 (s, 3H), 3.06 (d, J = 9.0 Hz, 1H), 2.92 (d, J = 8.8 Hz, 1H),2.13 (s, 3H), 2.08-2.00 (m, 2H). MS (m/z): 338.4 (M + H). 167 306

4-((1S,4S)-5-p-tolyl- 2,5-diazabicyclo[2.2.1] heptan-2-yl)benzoic acid¹H NMR (DMSO-d₆) δ (ppm): 7.65 (d, J = 9.8 Hz, 2H), 6.90 (d, J = 8.2 Hz,2H), 6.54 (d, J = 8.2 Hz, 2H), 6.45 (d, J = 8.4 Hz, 2H), 4.66 (s, 1H),4.55 (s, 1H), 3.54 (t, J = 8.3 Hz, 2H), 3.07 (d, J = 9.2 Hz, 1H), 2.90(d, J = 8.8 Hz, 1H), 2.11 (s, 3H), 2.04-1.98 (m, 2H). MS (m/z): 304.4(M + H) 168 307

N-hydroxy-N-methyl- 2-((1S,4S)-5-p-tolyl- 2,5-diazabicyclo[2.2.1]heptan-2- yl)pyrimidine-5- carboxamide (DMSO)

 (ppm) 1H: 10.18 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 6.95 (d, J = 8.2Hz, 2H), 6.52 (d, J = 8.2 Hz, 2H), 5.00 (s, 1H), 4.59 (s, 1H), 3.64 (d,J = 8.2 Hz, 1H), 3.60-3.47 (m, 2H), 3.21 (s, 3H), 2.94 (d, J = 9.0 Hz,2H), 2.18 (s, 3H), 2.12-2.03 (m, 2H). LRMS (ESI): (calc.) 339.2 (found)340.4 (MH)+ 169 308

N-hydroxy-N-methyl- 2-((1S,4S)-5-(3- (trifluoromethyl) phenyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)pyrimidine- 5-carboxamide (MeOD) □ (ppm)1H: 8.76 (s, 1H), 8.70 (s, 1H), 7.31 (t, J = 7.9 Hz, 1H), 6.88 (d, J =7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 5.15 (s, 1H), 4.70(s, 1H), 3.72 (dd, J = 9.0 and 1.6 Hz, 1H), 3.70-3.49 (m, 2H), 3.31 (s,3H), 3.14 (d, J = 9.0 Hz, 1H), 2.21-2.10 (m, 2H). LRMS(ESI): (calc.)393.1 (found) 394.4 (MH)+

Example 200(Z)-4-((5H-dibenzo[b,f]azepin-5-yl)methyl)-N-hydroxybenzamide (351) Step1: (Z)-methyl 4-((5H-dibenzo[b,f]azepin-5-yl)methyl)benzoate (350)

(Z)-5H-Dibenzo[b,f]azepine (100 mg, 0.52 mmol), dibutyltin dichloride(54 mg, 0.16 mmol) and methyl 4-formylbenzoate (260 mg, 1.60 mmol) werestirred in THF (2 mL) for 30 minutes. Phenylsilane was added and thereaction mixture was stirred for 3 days. The solvent was evaporated andthe residue was purified by flash chromatography (0% to 40% EtOAc inhexanes). The fractions containing some product were washed withNa₂S₂O₄. The layers were split and the organic layer was evaporated toafford title compound 350 (147 mg, 83%) as a yellow solid.

Step 2: (Z)-4-((5H-dibenzo[b,f]azepin-5-yl)methyl)-N-hydroxybenzamide(351)

Title compound 350 (147 mg, 0.43 mmol), hydroxylamine (50% in water, 6mL) and sodium hydroxide (138 mg, 3.40 mmol) were stirred in methanol (3mL) and THF (3 mL) at room temperature overnight. The organic solventwas evaporated and the precipitate was filtered off and washed with alittle bit of cold methanol to afford title compound 351 (39 mg, 26%) asa yellow solid. ¹H NMR (DMSO-d6) δ (ppm): 11.06 (s, 1H), 8.96 (s, 1H),7.57 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.21 (td, J=1.6 and 7.2Hz, 2H), 7.18-7.13 (m, 2H), 7.10 (dd, J=1.6 and 7.6 Hz, 2H), 6.6 (td,J=1.2 and 7.2 Hz, 2H), 6.85 (s, 2H), 5.00 (s, 2H). LRMS: 342.1 (calc)343.2 (found)

Example 201 Compound (353) Step 1: Compound (352)

To a suspension of sodium hydride (0.55 g, 14.0 mmol, 60% in oil, washedwith hexanes) in DMSO (20 mL) was added a solution of ethyl2-(diethoxyphosphoryl)acetate (2.8 mL, 14.0 mmol) in DMSO (5 mL). Themixture was stirred for 30 minutes. A solution of the ketone (2.5 g,12.1 mmol) in DMSO (20 mL) was added and the reaction mixture wasstirred at 100° C. for 30 hours. The reaction mixture was cooled down toroom temperature and poored into an ice-water mixture and stirredvigorously for 1 hour. The precipitate was then filtered and dried toafford title compound 352 (2.75 g, 82% crude yield) as a beige solid. MS(m/z): 277.0 (M+H).

Step 2: Compound (353)

Using Procedure B-3 (Table 5) with compound 352 the title compound 353was obtained (220 mg, 75%) as a yellow solid. ¹H NMR (DMSO-d₆) δ (ppm):10.7-10.4 (1H, br s), 8.9-8.7 (1H, br s), 7.44-7.25 (8H, m), 6.99 and6.91 (2H, AB doublet, J=12.1 Hz), 5.75 (1H, s). MS (m/z): 264.0 (M+H).

Example 202(E)-N-hydroxy-3-((Z)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)acrylamide(356) Step 1: (Z)-8-bromo-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one(354)

(2-Amino-4-bromophenyl)(phenyl)methanone (1.75 g, 10 mmol), ethyl2-aminoacetate (2.23 g, 16 mmol) and pyridine (40 mL) were stirredtogether at 80° C. for about 3 days. The pyridine was evaporated and theresidue was triturated in 5% methanol in ethyl acetate to afford titlecompound 354 (1.6 g, 51%) as a yellow solid.

Step 2: (E)-methyl3-((Z)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)acrylate(355)

Title compound 354 (400 mg, 1.28 mmol), methyl acrylate (132 mg, 1.54mmol), Pd2(dba)₃ (16 mg, 0.038 mmol), POT (24 mg, 0.07 mmol) andtriethylamine (0.446 mL, 3.2 mmol) were mixed in DMF (15 mL). Themixture was degassed with nitrogen for 5 minutes and the reactionmixture was heated to 100 oC for 2 hours. The DMF was removed and theresidue was partitioned between ethyl acetate and water. The 2 layerswere split and the aqueous layer was extracted with 2 other portions ofethyl acetate. The combined organic layers were washed with brine, driedover MgSO4, filtered and evaporated. The crude product was purified byflash chromatography (50% to 65% ethyl acetate in hexanes) to affordtitle compound 355 (135 mg, 33%) as a light yellow solid. ¹H NMR(DMSO-d₆) δ (ppm): 10.56 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d,J=16.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.24 (d,J=6.4 Hz, 2H), 7.16 (td, J=7.5, 1.0 Hz, 1H), 6.70 (d, J=16.2 Hz, 1H),4.12 (s, 2H), 3.72 (s, 3H).

Step 3:(E)-N-hydroxy-3-((Z)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)acrylamide(356)

Using Procedure B-3 (Table 5) with compound 355 the title compound 356was obtained (20 mg, 24%) as a yellow solid. ¹H NMR (DMSO-d₆) δ (ppm):10.54 (s, 1H), 7.61-7.53 (m, 3H), 7.50-7.44 (m, 3H), 7.26-7.22 (m, 2H),7.17 (td, J=7.2, 1.0 Hz, 1H), 6.51 (d, J=5.9 Hz, 1H), 4.12-4.01 (br s,2H). MS (m/z): 322.2 (M+H).

Example 203(E)-N-hydroxy-3-((Z)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)acrylamide(359) Step 1:(Z)-8-bromo-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (357)

Title compound 354 (3.1 g, 11.8 mmol), sodium hydride (565 mg, 14.14mmol) and methyliodide (0.88 mL, 14.14 mmol) were stirred together inDMF (60 mL) at room temperature for 6 hours. DMF was removed and theresidue was partitioned in EtOAc and water. The organic layer was dried,filtered and evaporated. The crude product was purified by flashchromatography (3:1 to 1:2 hexane:ethyl acetate) to afford titlecompound 357 (2.3 g, 60%) as a white solid.

Step 2: (E)-methyl3-((Z)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)acrylate(358)

Using Procedure E-3 (Table 5) with compound 357 the title compound 358was obtained (380 mg, 45%) as a light brown solid. ¹H NMR (DMSO-d₆) δ(ppm): 7.78 (d, J=8.2 Hz, 2H), 7.69 (d, J=16.0 Hz, 1H), 7.67-7.63 (m,1H), 7.58-7.55 (m, 3H), 7.26-7.25 (m, 2H), 6.71 (d, J=16.0 Hz, 1H), 4.56(d, J=10.8 Hz, 1H), 3.73 (d, J=10.0 Hz, 1H), 3.72 (s, 3H), 3.30 (s, 3H).

Step 3:(E)-N-hydroxy-3-((Z)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)acrylamide(359)

Using Procedure B-3 (Table 5) with compound 358 the title compound 359was obtained (60 mg, 17%) as a beige solid. ¹H NMR (CD₃OD) δ (ppm):7.70-7.56 (m, 7H), 7.29 (d, J=4.1 Hz, 2H), 6.55 (d, J=15.8 Hz, 1H), 4.63(d, J=10.8 Hz, 1H), 3.83 (d, J=10.8 Hz, 1H), 3.43 (s, 3H). MS (m/z):336.1 (M+H).

Example 204(Z)-N-hydroxy-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)propanamide(361) Step 1: (Z)-methyl3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)propanoate(360)

Title compound 358 (410 mg, 1.23 mmol) was dissolved in methanol (30 mL)and Pd(C) (250 mg) was added. The reaction mixture was stirred underhydrogen atmosphere for 2 hours. The catalyst was filtered off and thefiltrate was evaporated to afford title compound 360 (370 mg, 90%) as aclear oil. ¹H NMR (DMSO-d6) δ (ppm): 7.65-7.61 (m, 1H), 7.55 (d, J=8.0Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.28-7.22 (m, 4H), 4.51 (d, J=10.6 Hz,1H), 3.69 (d, J=10.8 Hz, 1H), 3.56 (s, 3H), 3.29 (s, 3H), 2.88 (t, J=7.5Hz, 2H), 2.64 (t, J=7.5 Hz, 2H).

Step 2:(Z)-N-hydroxy-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-8-yl)propanamide(361)

Using Procedure B-3 (Table 5) with compound 360 the title compound 361was obtained (50 mg, 14%) as a clear oil. ¹H NMR (CD₃OD) δ (ppm):7.68-7.63 (m, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H),7.29-7.23 (m, 4H), 4.58 (d, J=11.0 Hz, 1H), 3.79 (d, J=11.0 Hz, 1H),3.42 (s, 3H), 2.97 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.8 Hz, 2H). MS (m/z):338.2 (M+H).

Example 205(Z)-N-hydroxy-6-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)hexanamide(364) Step 1: (Z)-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (362)

Using Procedure D-3 (Table 5) with (2-aminophenyl)(phenyl)methanone thetitle compound 362 was obtained (2.0 g, 34%) as a light yellow solid. ¹HNMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.56 (ddd, J=8.5, 7.1, 1.7 Hz,1H), 7.50-7.39 (m, 5H), 7.25-7.21 (m, 2H), 7.18-7.14 (m, 1H), 4.20-4.18(m, 2H).

Step 2: (Z)-ethyl6-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)hexanoate(363)

Title compound 362 (400 mg, 1.69 mmol), ethyl 6-bromohexanoate (0.3 mL,1.69 mmol) and potassium carbonate (584 mg, 4.23 mmol) were mixed in DMF(20 mL) and the reaction mixture was heated to 80 oC for 24 hours. TheDMF was removed and the residue was partitioned between water and ethylacetate. The 2 layers were split and the aqueous layer was extractedwith 2 other portions of ethyl acetate. The combined organic layers werewashed with brine, dried, filtered and evaporated. The crude product waspurified by flash chromatography (2:1 to 1:2, hexanes:ethyl acetate) toafford title compound 363 (400 mg, 63%) as a clear oil.

Step 3:(Z)-N-hydroxy-6-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)hexanamide(364)

Using Procedure B-3 (Table 5) with compound 363 the title compound 364was obtained (100 mg, 26%) as a yellow oily solid. ¹H NMR (CD₃OD) δ(ppm): 7.69-7.61 (m, 2H), 7.55-7.49 (m, 3H), 7.47-7.42 (m, 2H),7.32-7.25 (m, 2H), 4.58 (d, J=10.6 Hz, 1H), 4.43-4.36 (m, 1H), 3.81 (d,J=10.7 Hz, 1H), 3.78-3.71 (m, 1H), 1.85 (t, J=7.7 Hz, 2H), 1.56-1.37 (m,4H), 1.16-1.09 (m, 2H). MS (m/z): 366.1 (M+H).

Example 206 (Z)-2-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxyacetamide (367)Step 1: (Z)-2-(5H-dibenzo[b,f]azepin-5-yl)acetonitrile (365)

(Z)-5H-dibenzo[b,f]azepine (0.1 g, 0.5 mmol), tetrabutylammonium sulfate(0.35 g, 1.0 mmol), 2-bromoacetonitrile (0.4 mL, 5.0 mmol) and 50%aqueous sodium hydroxide (1 mL) were mixed in DCM (1 mL) and thereaction mixture was stirred for 5 days. The mixture was diluted inwater and the aqueous layer was extracted with DCM (2 times). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated. The crude product was purified by flash chromatography (0%to 50% ethyl acetate in hexanes) to afford title compound 365 (60 mg,50%). ¹H NMR (CDCl₃) δ (ppm): 7.36-7.31 (m, 2H), 7.26-7.23 (m, 2H),7.17-7.11 (m, 4H), 6.76 (s, 2H), 4.47 (s, 2H).

Step 2: (Z)-methyl 2-(5H-dibenzo[b,f]azepin-5-yl)acetate (366)

To title compound 365 (60 mg, 0.26 mmol) was added conc HCl and methanoland the reaction mixture was stirred for 5 hours. The mixture wasconcentrated and the residue was partitioned between sodium bicarbonateand ethyl acetate. The layers were split and the aqueous layer wasextracted another time with ethyl acetate. The combined organic layerswere evaporated to afford title compound 366 (40 mg, 58% crude yield).MS (m/z): 266.0 (M+H).

Step 3: (Z)-2-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxyacetamide (367)

Using Procedure B-3 (Table 5) with compound 366 the title compound 367was obtained (30 mg, 24%) as beige solid. ¹H NMR (CDCl₃) δ (ppm): 7.28(2H, t, J=7.1 Hz), 7.16-7.11 (4H, m), 7.04 (2H, t, J=7.1 Hz), 6.83 (2H,s), 4.42 (2H, s). MS (m/z): 267.0 (M+H).

Example 207 Compound (370) Step 1: Compound (368)

Ketone (3.0 g, 14.4 mmol), hydroxylamine hydrochloride (3.0 g) andpyridine (3 mL) were mixed in ethanol (3 mL) and the reaction mixturewas refluxed for 4 hours. The ethanol and the pyridine were evaporatedand the residue was diluted with water. The aqueous layer was extractedtwice with ethyl acetate. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated. The residuewas purified by trituration in ethyl acetate (15 mL) and hexanes (5 mL),filtered, washed with hexanes and dried to afford title compound 368(1.2 g, 46%) as brown solid. MS (m/z): 223 (M+H).

Step 2: Compound (369)

Title compound 368 (100 mg, 0.45 mmol), potassium carbonate (187 mg,1.35 mmol) and methyl 8-bromooctanoate (0.14 mL, 0.67 mmol) were mixedin acetone (1 mL) and the reaction mixture was heated to 40° C. for 4hours. The mixture was cooled down and concentrated. PS trisamine (0.3g) and DCM were added to the residue and the mixture was stirred for 3hours. The mixture was filtered and concentrated to afford crude titlecompound 369 that was used directly to next step.

Step 3: Compound (370)

Using Procedure B-3 (Table 5) with compound 369 the title compound 370was obtained (67 mg, 39% for 2 steps). (CD₃OD) δ (ppm): 7.51 (dd, J=7.8,1.5 Hz, 1H), 7.30-7.25 (m, 4H), 7.24-7.15 (m, 2H), 7.13 (d, J=7.6 Hz,1H), 4.13 (t, J=6.5 Hz, 2H), 3.12-3.00 (m, 4H), 2.06 (t, J=7.5 Hz, 2H),1.67-1.56 (m, 4H), 1.40-1.20 (m, 6H). MS (m/z): 381.2 (M+H).

Example 208 Compound (373) Step 1: Compound (371)

Title compound 368 (50 mg, 0.224 mmol) and phosgene (107 mg, 0.448) weredissolved in methanol (5 mL). Sodium borohydride (8.5 mg, 2.24 mmol) wasadded portion wise and the reaction mixture was stirred for 5 minutes.The mixture was diluted with ethyl acetate. The organic layer was washedwith a solution of 5% NaOH in water (twice), water and brine, dried oversodium sulfate, filterer and evaporated to afford title compound 371.

Step 2: Compound (372)

Using Procedure A-3 (Table 5) with compound 371 the title compound 372was obtained (295 mg, 83%).

Step 3: Compound (373)

To a solution of potassium hydroxide (232 mg, 4.13 mmol) in methanol (10mL) was added the hydroxylamine hydrochloride (287 mg, 4.13 mmol)followed by a solution of title compound 372 (295 mg, 0.826 mmol) in THF(5 mL). The reaction mixture was stirred at r.t. for 1 hour. The mixturewas acidified with 40% HCl to reach pH=2. The precipitate was filteredand the solid was triturated in water, then in methanol and hexanes toafford title compound 373 (65 mg, 22%) as an off-white solid. ¹H NMR(MeOH-d₄) δ (ppm): 7.80 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H),7.42-7.38 (m, 4H), 7.33-7.27 (m, 4H), 5.49 (br s, 1H), 4.20 (s, 2H),3.44-3.42 (m, 2H), 3.08 (m, 2H). MS (m/z): 359.1 (M+H).

Example 209(E)-3-((Z)-5-(cyclopropylmethyl)-5H-dibenzo[b,f]azepin-2-yl)-N-hydroxyacrylamide(379) Step 1: (4aZ,10Z)-2H-dibenzo[b,f]azepin-2-one (374)

To a solution of Na₂HPO₄ (2.5 g, 9.32 mmol) in water (95 mL) was added(KSO₃)₂NO (1.8 g, 12.7 mmol). This solution was added to a solution ofthe (Z)-5H-dibenzo[b,f]azepine (0.5 g, 2.59 mmol) in acetone (50 mL).This reaction mixture was stirred at 4° C. over night. The solid wasfiltered and the filtrate was evaporated. The residue was dissolved inether and water. The 2 layers were split. The organic layer and thesolid were mixed and evaporated. The crude product was purified by flashchromatography to afford title compound 374 (170 mg, 34%). MS (m/z): 207(M+H). Step 2: (Z)-5H-dibenzo[b,f]azepin-2-ol (375)

Title compound 374 (170 mg, 0.82 mmol) was solubilized in CHCl₃ (5 mL)and a saturated solution of Na₂S2O₄ in water was added (20 mL). Themixture was stirred for 3 hours. The 2 layers were split and the organiclayer was dried over sodium sulfate, filtered and evaporated to affordtitle compound 375 (110 mg, 65%). MS (m/z): 209.9 (M+H).

Step 3: (Z)-5-(cyclopropylmethyl)-5H-dibenzo[b,f]azepin-2-ol (376)

Using Procedure A-3 (Table 5) with compound 375 the title compound 376was obtained (40 mg, 64%).

Step 4: (Z)-5-(cyclopropylmethyl)-5H-dibenzo[b,f]azepin-2-yltrifluoromethanesulfonate (377)

Title compound 376 (90 mg, 0.34 mmol) and2,6-di-tert-butyl-4-methylpyridine (105 mg, 0.44 mmol) were solubilizedin THF (0.5 mL). This solution was added to a solution oftrifluoromethanesulfonic anhydride (74 μL, 0.44 mmol) in THF (0.5 mL) at0° C. The flask was rinsed with THF (2×0.5 mL). The reaction mixture wasstirred at r.t. for 3 hours. More trifluoromethanesulfonic anhydride (15μL) was added and the mixture was stirred for 1 hour. A saturatedaqueous solution of sodium bicarbonate was added and the mixture wasstirred for 5 minutes prior to the extraction with DCM (2 times). Thecombined organic layers were evaporated and the residue was purified byflash chromatography (0% to 20% EtOAc in hexanes) to afford titlecompound 377 (190 mg) mixed with some base. MS (m/z): 396.1 (M+H).

Step 5: (E)-methyl3-((Z)-5-(cyclopropylmethyl)-5H-dibenzo[b,f]azepin-2-yl)acrylate (378)

Using Procedure E-3 (Table 5) with compound 377 the title compound 378was obtained (50 mg, 44%). MS (m/z): 332 (M+H). ¹H NMR (CDCl₃) δ (ppm):7.38 (d, J=16.0 Hz, 1H), 7.18 (dd, J=8.2, 2.2 Hz, 1H), 7.05-6.97 (m,2H), 6.84-6.75 (m, 4H), 6.53 (d, J=11.3 Hz, 1H), 6.46 (d, J=11.3 Hz,1H), 6.97 (d, J=16.0 Hz, 1H), 3.57 (s, 3H), 3.37 (d, J=4.7 Hz, 2H),0.83-0.79 (m, 1H), 0.24-0.19 (m, 2H), 0.04-0.00 (m, 2H).

Step 6:(E)-3-((Z)-5-(cyclopropylmethyl)-5H-dibenzo[b,f]azepin-2-yl)-N-hydroxyacrylamide(379)

Using Procedure B-3 (Table 5) with compound 378 the title compound 379was obtained (7 mg, 14%). ¹H NMR (CD₃OD) δ (ppm): 7.5-7.4 (2H, m),7.25-7.2 (2H, m), 7.05-7.0 (3H, m), 6.99-9.93 (1H, m), 6.75-6.65 (2H,observed 2d), 6.33 (1H, d, J=15.7 Hz), 3.57 (2H, d, J=6.4 Hz), 1.05-0.95(1H, m), 0.45-0.37 (2H, m), 0.25-0.18 (2H, m). MS (m/z): 333.1 (M+H).

Example 2104-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-6(11H)-yl)-N-hydroxybutanamide(385) Step 1: N-cyclopropyl-2-nitroaniline (380)

1-fluoro-2-nitrobenzene (1.85 mL, 175 mmol) and cyclopropanamine (2.43mL, 35 mmol) were stirred in DMSO for 3 hours. Water was added (250 mL)and the mixture was extracted with ether (2×250 mL). The combinedorganic extracts were washed with brine, dried over sodium sulfate,filtered and evaporated to afford title compound 380 (3.1 g, 99%) as anorange oil. MS (m/z): 178.9 (M+H). ¹H NMR (CDCl₃) δ (ppm): 8.15 (dd,J=8.6, 1.6 Hz, 1H), 8.09 (s, 1H), 7.49-7.45 (m, 1H), 7.32 (dd, J=8.6,1.4 Hz, 1H), 6.72-6.67 (m, 1H), 2.60-2.58 (m, 1H), 0.94-0.89 (m, 2H),0.68-0.64 (m, 2H).

Step 2: NI-cyclopropylbenzene-1,2-diamine (381)

Title compound 380 (3.1 g, 17.4 mmol) and palladium on charcoal 10% (0.3g, 10% w/w) were mixed in ethanol (100 mL) and the reaction mixture wasstirred under 45 PSI of hydrogen for 4 hours. The mixture was filteredto remove the catalyst and the filtrate was evaporated to afford titlecompound 381 as black oil that was used without further purification. MS(m/z): 148.9 (M+H).

Step 3: 2-chloro-N-(2-(cyclopropylamino)phenyl)nicotinamide (382)

To a solution of title compound 381 (0.83 g, 5.84 mmol) anddiisopropylethylamine (1.02 mL, 0.74 mmol) in THF (50 mL) was added asolution of 2-chloronicotinoyl chloride (1.03 g, 5.84 mmol) in THF at 0°C. The reaction mixture was stirred over night and concentrated. To theresidue was added a saturated solution of bicarbonate (3 mL) and thisaqueous layer was extracted with DCM (2×). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andevaporated. The solid was triturated in DCM (3 mL) and filtered. Thefiltrate was evaporated and purified by flash chromatography (0% to 80%ethyl acetate in hexanes). The 2 solids were mixed to afford titlecompound 382 (1.1 g, 65%) as a white solid. MS (m/z): 288.0 (M+H).

Step 4:11-cyclopropyl-6,11-dihydro-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-one(383)

Title compound 382 (0.7 g, 2.4 mmol), sodium hydride (0.292 g, 7.3 mmol)and pyridine (20 mL) were stirred together at 80° C. for 5 hours then atroom temperature over week-end. The reaction mixture was then pouredinto an ice-water mixture and stirred for 1 hour. The beige solid wasfiltered and the filtrate was extracted with ethyl acetate (2 times).The combined organic extracts were dried and concentrated. The residuewas purified by flash chromatography (10-70% ethyl acetate in hexanes).The 2 solids were mixed together to afford title compound 383 (0.51 g,85%) as a beige solid. MS (m/z): 251.9 (M+H).

Step 5: methyl4-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-6(11H)-yl)butanoate(384)

Using Procedure H-3 (Table 5) with compound 383 the title compound 384was obtained (50 mg, 71%). MS (m/z): 352 (M+H). ¹H NMR (CDCl₃) δ (ppm):8.38 (dd, J=4.8, 2.1 Hz, 1H), 8.04 (dd, J=7.6, 2.0 Hz, 1H), 7.47 (dd,J=7.9, 1.8 Hz, 1H), 7.24-7.13 (m, 3H), 7.02 (dd, J=7.6, 4.7 Hz, 1H),4.68-4.61 (m, 1H), 3.69-3.54 (m, 2H), 3.60 (s, 3H), 2.31-2.26 (m, 2H),1.96 (sept., J=6.9 Hz, 1H), 1.77-1.69 (m, 1H), 1.07-1.02 (m, 1H),0.93-0.87 (m, 1H), 0.66-0.60 (m, 1H), 0.51-0.45 (m, 1H).

Step 6:4-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin-6(11H)-yl)-N-hydroxybutanamide(385)

Using Procedure B-3 (Table 5) with compound 384 the title compound 385was obtained (24 mg, 49%). ¹H NMR (CD₃OD) δ (ppm): 8.36 (1H, dd, J=4.9,1.7 Hz), 8.00 (1H, dd, J=7.6, 1.7 Hz), 7.52 (1H, dd, J=8.1, 1.3 Hz),7.38 (1H, dd, J=8.0, 1.1 Hz), 7.26 (1H, td, J=7.8, 1.3 Hz), 7.23-7.17(1H, td observed), 7.12 (1H, dd, J=7.6, 4.9 Hz), 4.58-4.48 (1H, m),3.76-3.68 (1H, m), 3.60-3.55 (1H, m), 2.06 (2H, t, J=7.6 Hz), 1.95-1.80(1H, m), 1.79-1.73 (1H, m), 1.05-0.87 (2H, m), 0.60-0.42 (2H, m). MS(m/z): 353.1 (M+H).

Compound (388) Step 1: Compound (386)

Using Procedure A-3 (Table 5) with starting amine the title compound 386was obtained (71 mg, 40%). ¹H NMR (CD₃OD) δ (ppm): 7.61-7.53 (3H, m),7.35 (2H, d, J=8.2 Hz), 7.28-7.14 (8H, m), 6.48 (1H, d, J=15.9 Hz), 5.05(1H, s), 3.84 (2H, s), 3.65-3.52 (2H, m), 3.03-2.93 (2H, m). MS (m/z):368 (M−H).

Step 2: Compound (387)

Title compound 386 (71 mg, 0.19 mmol), DBU (30 μL, 0.20 mmol) and methyliodide (12 μL, 0.20 mmol) were stirred in acetonitrile (1 mL) for 30minutes. More DBU and methyl iodide were added and the reaction mixturewas stirred over week-end. The mixture was concentrated and the residuewas partitioned between saturated solution of bicarbonate and ethylacetate. The aqueous layer was extracted with another portion of ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and evaporated to afford crude compound 387that was used directly for next step.

Step 3: Compound (388)

Using Procedure B-3 (Table 5) with compound 387 the title compound 388was obtained (50 mg, 50%). ¹H NMR (CD₃OD) δ (ppm): 7.70-7.55 (3H, m),7.47 (2H, d, J=7.8 Hz), 7.42-7.34 (4H, m), 7.33-7.21 (5H, m), 6.56 (1H,d, J=15.9 Hz), 5.49 (1H, br s), 4.16 (1H, br s), 3.50-3.36 (2H, m),3.25-2.98 (2H, m). MS (m/z): 385.1 (M+H).

Example 212(Z)-2-(4-((5H-dibenzo[b,f]azepin-5-yl)methyl)phenyl)-N-hydroxyacetamide(393) Step 1: (Z)-methyl 4-((5H-dibenzo[b,f]azepin-5-yl)methyl)benzoate(389)

Using Procedure A-3 (Table 5) with (Z)-5H-dibenzo[b,f]azepine the titlecompound 389 was obtained (1.9 g mg, 100%). MS (m/z): 342.0 (M+H).

Step 2: (Z)-methyl 4-((5H-dibenzo[b,f]azepin-5-yl)methyl)benzoate (390)

Title compound 389 (1.0 g, 2.93 mmol) and lithium hydroxide (2N inwater, 10 mL) were stirred in a mixture of THF (20 mL) and methanol (20mL) over night. The reaction mixture was then heated to 50° C. for 3hours. The solvent were evaporated and the residue was acidified topH=4-5 with 3N HCl. The solid was filtered, washed with water and dried.The mother liquor was extracted with ethyl acetate (3 times). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered and evaporated. The residue was triturated in etherand the 2 solids were mixed together to afford title compound 390 (0.71g, 74%) as a brown solid. ¹H NMR (DMSO-d₆) δ (ppm): 7.74 (2H, d, J=7.8Hz), 7.48 (2H, d, J=7.6 Hz), 7.22-7.05 (6H, m), 6.98-6.91 (2H, m), 6.83(2H, s), 5.00 (2H, s). MS (m/z): 326.1 (M−H).

Step 3: (Z)-4-((5H-dibenzo[b,f]azepin-5-yl)methyl)benzoyl chloride (391)

The title compound 390 (0.72 g, 2.2 mmol) and the oxalyl chloride (0.58mL, 6.6 mmol) were mixed in DCM (10 mL) and few drops of DMF was added.The reaction mixture was stirred for 30 minutes and the solvent wasevaporated (and stripped with toluene twice) to afford title compound391 that was used crude for next step.

Step 4: (Z)-methyl2-(4-((5H-dibenzo[b,f]azepin-5-yl)methyl)phenyl)acetate (392)

The nitroso methyl urea (4.3 g, 42 mmol) was combined with potassiumhydroxide (40% in water, 7.75 mL) in ether at 0° C. The reaction mixturewas stirred for 30 minutes and cooled to −78° C. The organic phase wasdecanted to afford a solution of diazomethane in ether. To half of thissolution at 0° C. was added the title compound 391 (2.2 mmol) in THF (20mL) and this reaction mixture was stirred at 0° C. for 2 hours. Theexcess of diazomethane was evaporated (flow of air) and a saturatedsolution of bicarbonate was added. This mixture was extracted with ethylacetate (2 times). The combined organic extracts were washed with brine,dried over sodium sulfate, filtered and evaporated. The residue waspurified by flash chromatography (0% to 50% ethyl acetate in hexanes) toafford title compound 392 (0.40 g, 50%) as a solid. MS (m/z): 356.1(M+H).

Step 5:(Z)-2-(4-((5H-dibenzo[b,f]azepin-5-yl)methyl)phenyl)-N-hydroxyacetamide(393)

Using Procedure B-3 (Table 5) with compound 392 the title compound 393was obtained (40 mg, 36%) as a yellow solid. ¹H NMR (DMSO-d₆) δ (ppm):10.57 (1H, s), 8.74 (1H, s), 7.31 (2H, d, J=8.2 Hz), 7.19 (2H, td,J=7.2, 1.6 Hz), 7.11 (2H, d, J=7.2 Hz), 7.10-7.04 (4H, m), 6.92 (2H, m),6.81 (2H, s), 4.89 (2H, s), 3.13 (2H, s). MS (m/z): 357.1 (M+H).

Step 1: Compound (394)

Title compound 368 (0.26 g, 1.16 mmol) and potassium tert-butoxide(0.143 g, 1.17 mmol) were stirred in THF (1 mL) for 20 minutes. Asolution of ethyl 4-fluorobenzoate (0.171 mL, 1.16 mmol) in DMSO (0.3mL) was added. The reaction mixture was stirred 1 hour at roomtemperature, 1 hour at 50° C. and 2 hours at 75° C. The mixture wasdiluted with ethyl acetate. This organic layer was washed with water (3times) and brine, dried over sodium sulfate, filtered and evaporated.The crude was purified by flash chromatography (0% to 30% ethyl acetatein hexanes) to afford title compound 394 (0.1 g, 23%). MS (m/z): 372(M+H).

Step 2: Compound (395)

Using Procedure B-3 (Table 5) with compound 394 the title compound 395was obtained (71 mg, 73%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.13 (1H, s), 8.94 (1H, s), 7.74 (2H, d, J=8.8 Hz), 7.67 (1H, d, J=7.4Hz), 7.42-7.34 (4H, m), 7.32-7.26 (2H, m), 7.26-7.19 (3H, m), 3.21-2.99(4H, m). MS (m/z): 359.0 (M+H).

Compound (397) Step 1: Compound (396)

The amine (0.4 g, 1.9 mmol) and the sodium hydride (60% in oil, 84 mg,2.1 mmol) were stirred in THF (2 mL) for 1 hour. To this mixture at 0°C. was added a suspension of ethyl2-(methylsulfonyl)pyrimidine-5-carboxylate (0.754 g, 1.9 mmol) in THF (1mL). The reaction mixture was stirred at room temperature for 1 hour.Some water was added and the solid was filtered and discard. Thefiltrate was extracted with ethyl acetate (2 times. The combined organicextracts were washed with brine, dried over sodium sulfate, filtered andevaporated. The crude was purified by flash chromatography (0% to 100%ethyl acetate in hexanes) then with HPLC to afford title compound 396(15 mg, 2.5% yield) as a white solid. MS (m/z): 360.1 (M+H).

Step 2: Compound (397)

Using Procedure B-3 (Table 5) with compound 396 the title compound 397was obtained (8 mg, 57%) as a white solid. ¹H NMR (MeOD) δ (ppm): 8.62(2H, s), 7.44 (2H, d, J=7.1 Hz), 7.17-7.09 (6H, m), 6.66 (1H, s),3.38-3.30 (2H, m), 3.28-3.18 (2H, m). MS (m/z): 345.1 (M−H).

Example 2157-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-N-hydroxyheptanamide (400) Step1: 1011-dihydrodibenzo[b,f][1,4]oxazepine (398)

Dibenzo[b,f][1,4]oxazepin-11(10H)-one (1.001 g, 4.7 mmol) was dissolvedin THF (20 mL) and the borane (2M in THF, 20 mL, 40.0 mmol) was added.The reaction mixture was refluxed for 3 hours. The mixture was cooleddown to room temperature and an excess of ethanol was added to quenchthe reaction. The resulting mixture was refluxed for 2 hours. Themixture was cooled down and concentrated in vacuo. The residue wasdissolved in ethyl acetate and the organic layer was washed with waterand brine, dried over sodium sulfate, filtered and evaporated to affordtitle compound 398 (0.945 g, quantitative). MS (m/z): 198.1 (M+H). ¹HNMR (CD₃OD) δ (ppm): 7.29-7.19 (m, 2H), 7.16-7.04 (m, 2H), 7.01-6.99 (m,1H), 6.82-6.78 (m, 1H), 6.63-6.59 (m, 2H), 4.88 (s, 1H), 4.39 (s, 2H).MS (m/z): 198.1 (M+H).

Step 2: ethyl 7-(dibenzo[b,f][1,4]oxazepin-10(1H)-yl)heptanoate (399)

Title compound 398 (0.304 g, 1.54 mmol) was dissolved in acetonitrile(5.0 mL) and the ethyl 7-iodoheptanoate (0.613 g, 2.16 mmol) and thepotassium carbonate (0.639 g, 4.62 mmol) were added. The reactionmixture was stirred at 70° C. for 60 hours. The mixture was cooled downand diluted with ethyl acetate. The organic phase was washed with waterand brine, dried over sodium sulfate, filtered and evaporated. Theresidue was purified by flash chromatography with 10% ethyl acetate inhexanes to afford title compound 399 (201 mg, 37%). MS (m/z): 354.2(M+H).

Step 3: 7-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-N-hydroxyheptanamide(400)

Using Procedure B-3 (Table 5) with compound 399 the title compound 400was obtained (21 mg, 10%) as an oil. ¹H NMR (400 MHz, CD₃OD) δ (ppm):7.71 (m, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.52-7.48 (m, 2H), 7.43 (d, J=7.8Hz, 1H), 7.39-7.36 (m, 2H), 7.27 (t, J=7.4 Hz, 1H), 5.01 (s, 2H), 3.56(t, J=8.0 Hz, 2H), 2.15 (br s, 2H), 1.73-1.70 (m, 2H), 1.59-1.55 (m,2H), 1.31 (br s, 4H). MS (m/z): 341.1 (M+H).

Example 216N-hydroxy-N-(6-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)hexyl)formamide(404) Step 1: 10-(6-bromohexyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one(401)

Using Procedure H-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-onethe title compound 401 was obtained (740 mg, 83%) as a colorless oil. MS(m/z): 374.1 (M+H).

Step 2:10-(6-(benzyloxyamino)hexyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (402)

Using Procedure I-3 (Table 5) with compound 401 the title compound 402was obtained (648 mg, 79%) as a colorless oil. MS (m/z): 417.3 (M+H).

Step 3:N-(benzyloxy)-N-(6-(11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)hexyl)formamide(403)

1,1′-Carbonyldiimidazole (1.26 g, 7.8 mmol) was dissolved in THF (15 mL)and the mixture was cooled at 0° C. Title compound 402 (0.646 g, 1.56mmol) and formic acid in solution in THF (5 mL) was added. The reactionmixture was stirred at room temperature for 3 hours then diluted inethyl acetate. The organic phase was washed with a saturated aqueoussolution of bicarbonate, water and brine, then evaporated. The residuewas purified by flash chromatography (30-50% ethyl acetate in hexanes)to afford title compound 403 (348 mg, 50%) as a colorless oil. MS (m/z):445.2 (M+H).

Step 4:N-hydroxy-N-(6-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)hexyl)formamide(404)

Title compound 403 (348 mg, 0.783 mmol) was dissolved in methanol (10mL). The 10% palladium on charcoal (120 mg, 33% by wt) was added. Thereaction mixture was stirred for 3 hours under 1 atmosphere of hydrogenat room temperature. The reaction mixture was filtered to remove thecatalyst and the filtrate was evaporated. The residue was partitionedbetween ethyl acetate and water. The organic layer was dried over sodiumsulfate, filtered and evaporated to afford title compound 404 (18 mg,6%) as a white solid. ¹H NMR (CD₃OD) δ (ppm): 8.24, 7.89 (2s, rotamers,1H), 7.74 (d, J=7.6 Hz, 1H), 7.54-7.46 (m, 2H), 7.33 (dt, J=7.4, 2.0 Hz,1H), 7.28-7.21 (m, 4H), 4.19 (br s, 2H), 3.50 (t, J=6.8 Hz, 1H), 3.44(t, J=6.8 Hz, 1H), 1.70-1.55 (m, 4H), 1.44-1.29 (m, 4H). MS (m/z): 355.2(M+H).

Example 2172-(dipyridin-2-ylmethylamino)-N-hydroxypyrimidine-5-carboxamide (407)Step 1: dipyridin-2-ylmethanamine (405)

Dipyridin-2-ylmethanone oxime (500 mg, 2.510 mmol) and ammonium acetatewere solubilized in ethanol and the mixture was reflux for 3 hoursadding portion of zinc at 0 h, 1 h and 2 h. The reaction mixture wascooled down to room temperature and stirred over night. The pH wasadjusted to 12 with sodium hydroxide and the mixture was filteredthrough celite. The mixture was diluted with ethyl acetate and theorganic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated to afford title compound 405 (282 mg, 61%) as alight yellow oil. MS (m/z): 186.2 (M+H). ¹H NMR (CDCl₃) δ (ppm):8.50-8.49 (m, 2H), 7.56 (td, J=7.7, 1.8 Hz, 2H), 7.33 (dt, J=8.0, 0.9Hz, 2H), 7.08 (ddd, J=7.4, 4.9, 1.2 Hz, 2H), 5.26 (s, 1H), 2.38 (s, 2H).

Step 2: ethyl 2-(dipyridin-2-ylmethylamino)pyrimidine-5-carboxylate(406)

Using Procedure Y-3 (Table 5) with compound 405 the title compound 406was obtained (27 mg, 10%) as a yellow solid. MS (m/z): 336.2 (M+H).

Step 3: 2-(dipyridin-2-ylmethylamino)-N-hydroxypyrimidine-5-carboxamide(407)

Using Procedure B-3 (Table 5) with compound 406 the title compound 407was obtained (8 mg, 31%) as a yellow solid. ¹H NMR (CD₃OD) δ (ppm): 8.65(bs, 2H), 8.54 (d, J=4.8 Hz, 2H), 7.79 (dt, J=2 Hz, 7.6 Hz, 2H), 7.56(d, J=7.6 Hz, 2H), 7.31 (dd, J=2 Hz, 6.8 Hz, 2H), 6.43 (s, 1H). MS(m/z): 323.4 (M+H).

Example 218N-hydroxy-7-(11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-yl)heptanamide(411) Step 1: methyl 2-(2-nitrophenylthio)benzoate (408)

A solution of 2-mercaptobenzoic acid (6.0 g, 39.0 mmol) indimethylacetamide (20 mL) was added to a suspension of sodium hydride(60% in oil, 3.1 g, 77.5 mmol) in dimethylacetamide (15 mL). The mixturewas stirred for 5 minutes and 1-fluoro-2-nitrobenzene (5.0 g, 35.5 mmol)was added. The reaction mixture was heated at 80° C. for one hour. Themixture was cooled down to room temperature and methyl iodide (7.3 mL,117.15 mmol) was added. The reaction mixture was stirred at roomtemperature 16 hours. The mixture was then poor into water and extractedwith a mixture of 75% ethyl acetate in hexanes (3 times). The combinedorganic layers were washed with water and brine, dried over sodiumsulfate, filtered and evaporated. The residue was dissolved in a minimumamount of dichloromethane and hexanes was added to precipitate theproduct. The solid was filtered and dried to afford title compound 408(7.81 g, 76%) as a yellow solid. MS (m/z): 312.2 (M+H).

Step 2: dibenzo[b,f][1,4]thiazepin-11(10H)-one (409)

Using Procedure J (Table 1) with compound 408 followed by procedure K(Table 1), the title compound 409 was obtained (1.15 g, 40%) as a whitesolid. MS (m/z): 228.2 (M+H). ¹H NMR (DMSO-d₆) δ (ppm): 10.70 (s, 1H),7.68 (ddd, J=7.4, 1.9, 0.5 Hz, 1H), 7.57-7.42 (m, 4H), 7.36 (ddd, J=8.0,7.3, 1.5 Hz, 1H), 7.23 (dd, J=8.0, 1.2 Hz, 1H), 7.15 (td, J=7.5, 1.4 Hz,1H).

Step 3: ethyl 7-(11-oxodibenzo[b,f][1,4]thiazepin-10(11H)-yl)heptanoate(410)

Title compound 409 (0.403 g, 1.77 mmol) was dissolved in DMF (5.0 mL)and sodium hydride (60% in oil, 0.0.086 g, 2.13 mmol) was added. Thereaction mixture was stirred at 50° C. for 30 minutes. Ethyl7-bromoheptanoate (0.631 g, 2.66 mmol) was added and the reactionmixture was stirred at 50° C. for 16 hours. The mixture was cooled downto room temperature and quenched with water. The aqueous layer wasextrated 3 times with at mixture of 75% ethyl acetate in hexanes. Thecombined organic extracts were washed with water and brine, dried oversodium sulfate, filtered and evaporated. The residue was purified byflash chromatography (30% ethyl acetate in hexanes) to afford titlecompound 410 (470 mg, 69%). MS (m/z): 384.4 (M+H).

Step 4:N-hydroxy-7-(11-oxodibenzo[b,f][1,4]thiazepin-10(1H)-yl)heptanamide(411)

Using Procedure B-3 (Table 5) with compound 410 the title compound 411was obtained (220 mg, 48%) as a white solid. ¹H NMR (CD₃OD) δ (ppm):7.63-7.59 (m, 2H), 7.52-7.46 (m, 2H), 7.42-7.34 (m, 3H), 7.19 (td,J=7.4, 1.4 Hz, 1H), 4.70 (dt, J=13.7, 1.4 Hz, 1H), 3.67 (ddd, J=13.7,7.4, 5.9 Hz, 1H), 2.04 (t, J=7.0 Hz, 2H), 1.65-1.52 (m, 4H), 1.44-1.22(m, 4H). MS (m/z): 371.4 (M+H).

Example 219 Compound (414) Step 1: Compound (414)

2-Aminophenol (0.676 g, 6.2 mmol) was dissolved in pyridine (4.0 mL) andthe 2-fluorobenzene-1-sulfonyl chloride (1.80 mL, 13.6 mmol) was added.The reaction mixture was stirred at room temperature for 20 hours then10% HCl (20 mL) was added and the mixture was stirred at roomtemperature 24 hours. The mixture was diluted with ethyl acetate (and abit of methanol). The organic layer was washed with 10% HCl (5 times),brine, dried over sodium sulfate, filtered and evaporated. The residuewas dissolved in ethanol (20 mL) and potassium hydroxide in water (4M, 6mL) was added. This reaction mixture was stirred at 100 oC in a sealedtube for 24 hours. The mixture was cooled down to room temperature andthe pH was adjusted to pH=2 with 10% HCl. The aqueous layer wasextracted twice with ethyl acetate. The combined organic layers werewashed with water and brine, dried over sodium sulfate, filtered andevaporated. The residue was diluted with pyridine and cesium carbonatewas added (2.02 g, 6.2 mmol). The reaction mixture was stirred at 130 oCfor 36 hours. The mixture was cooled down to room temperature and the pHwas adjusted to pH=2 with 3N HCl. The aqueous layer was extracted withethyl acetate (3×). The combined organic extracts were washed with waterand brine, dried over sodium sulfate, filtered and evaporated. The crudewas purified by flash chromatography (40% ethyl acetate in hexanes) thentriturated in a mixture of 30% ethyl acetate in hexanes to afford titlecompound 412 (685 mg, 45%) as a white solid. MS (m/z): 246.0 (M−H). ¹HNMR (DMSO-d₆) δ (ppm): 10.88 (s, 1H), 7.78 (dd, J=7.7, 1.5 Hz, 1H), 7.72(ddd, J=8.1, 7.4, 1.7 Hz, 1H), 7.51 (dd, J=8.2, 0.8 Hz, 1H), 7.42 (td,J=7.6, 1.2 Hz, 1H), 7.39-7.35 (m, 1H), 7.20-7.15 (m, 2H), 7.08-7.05 (m,1H).

Step 2: Compound (413)

Using Procedure H-3 (Table 5) with compound 412 the title compound 413was obtained (536 mg, 94%) as a white solid. MS (m/z): 404.2 (M+H). ¹HNMR (DMSO-d₆) δ (ppm): 7.80 (dd, J=7.9, 1.7 Hz, 1H), 7.68 (ddd, J=8.4,7.2, 1.8 Hz, 1H), 7.50-7.43 (m, 4H), 7.40-7.33 (m, 2H), 4.02 (q, J=7.1Hz, 2H), 3.56 (t, J=7.1 Hz, 2H), 2.22 (t, J=7.4 Hz, 2H), 1.49-1.40 (m,4H), 1.33-1.18 (m, 4H), 1.15 (t, J=7.1 Hz, 3H).

Step 3: (414)

Using Procedure B-3 (Table 5) with compound 413 the title compound 414was obtained (439 mg, 85%) as a white solid. ¹H NMR (CD₃OD) δ (ppm):7.80 (dd, J=8.0, 2.0 Hz, 1H), 7.61 (ddd, J=8.4, 6.8, 1.2 Hz, 1H),7.46-7.41 (m, 3H), 7.38-7.30 (m, 3H), 3.62 (t, J=7.2 Hz, 2H), 2.06 (t,J=7.2 Hz, 2H), 1.61-1.51 (m, 4H), 1.44-1.28 (m, 4H). MS (m/z): 391.3(M+H).

Example 220N-hydroxy-3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)methyl)phenyl)propanamide(418) Step 1: 10-(4-iodobenzyl)dibenzo[b,f][1,4]oxazepin-11 (10H)-one(415)

Using Procedure H-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-oneand 1-(bromomethyl)-4-iodobenzene the title compound 415 was obtained(1.92 g, 78%) as beige foam. MS (m/z): 500 (M−H). ¹H NMR (CD₃OD) δ(ppm): 7.81 (dd, J=8.0, 1.8 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.55 (td,J=7.8, 1.8 Hz, 1H), 7.38-7.36 (m, 1H), 7.31-7.27 (m, 3H), 7.19-7.12 (m,2H), 7.10 (d, J=8.4 Hz, 2H), 5.33 (s, 2H).

Step 2: (E)-ethyl3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)methyl)phenyl)acrylate(416)

Using Procedure E-3 (Table 5) with compound 415 the title compound 416was obtained (743 mg, 78%) as pink foam. MS (m/z): 400.4 (M+H).

Step 3: ethyl3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)methyl)phenyl)propanoate(417)

Compound 416 (0.364 g, 0.912 mmol) was dissolved in ethanol (10.0 mL)and the palladium on charcoal (0.037 g, 10% w/w) was added. The reactionmixture was stirred over 1 atmosphere of hydrogen at room temperaturefor 1 hour. The catalyst was filtered and the filtrate was concentratedto afford title compound 417 (346 mg, 95%) that was used crude for nextstep. MS (m/z): 402.4 (M+H).

Step 4:N-hydroxy-3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)methyl)phenyl)propanamide(418)

Using Procedure B-3 (Table 5) with compound 417 the title compound 418was obtained (132 mg, 40%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):10.33 (s, 1H), 8.68 (s, 1H), 7.74 (dd, J=7.6, 1.6 Hz, 1H), 7.60-7.56 (m,1H), 7.48-7.44 (m, 1H), 7.36-7.28 (m, 3H), 7.19-7.10 (m, 6H), 5.31 (s,2H), 2.73 (t, J=7.2 Hz, 2H), 2.20 (t, J=7.2 Hz, 2H). MS (m/z): 389.4(M+H).

Example 2214-(2-(7-chloro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)-N-hydroxybenzamide(421) Step 1: methyl 2-(5-chloro-2-nitrophenoxy)benzoate (419)

Methyl 2-hydroxybenzoate (2.75 mL, 21.3 mmol) and4-chloro-2-fluoro-1-nitrobenzene (1.85 g, 10.6 mmol) were dissolved inacetonitrile (25.0 mL). The cesium carbonate (6.94 g, 21.3 mmol) wasadded and the reaction mixture was stirred at 80° C. for 24 hours. Themixture was cooled down to room temperature then poor into ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate, filtered and evaporated. The crude was purified by flashchromatography (10-30% ethyl acetate in hexanes) to afford titlecompound 419 (2.55 g, 78%). MS (m/z): 308.2 (M+H). ¹H NMR (DMSO-d₆) δ(ppm): 8.14 (d, J=8.8 Hz, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.74 (ddd,J=8.1, 7.4, 1.8 Hz, 1H), 7.47 (td, J=7.6, 1.2 Hz, 1H), 7.39 (dd, J=8.8,2.2 Hz, 1H), 7.36 (dd, J=8.3, 1.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 3.69(s, 3H).

Step 2: 7-chlorodibenzo[b,f][1,4]oxazepin-11(10H)-one (420)

Using Procedure AB-3 (Table 5) with compound 419 the title compound 420was obtained (200 mg, 10%) as white solid. MS (m/z): 246.1 (M+H). ¹H NMR(DMSO-d₆) δ (ppm): 10.63 (s, 1H), 7.77 (dd, J=7.8, 1.6 Hz, 1H), 7.64(ddd, 8.2, 7.3, 1.8 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.38 (dd, J=8.1,0.9 Hz, 1H), 7.34 (td, J=7.5, 1.2 Hz, 1H), 7.28 (dd, J=8.6, 2.3 Hz, 1H),7.17 (d, J=8.6 Hz, 1H).

Step 3: methyl4-(2-(7-chloro-11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)ethoxy)benzoate(421)

Using Procedure H-3 (Table 5) with compound 420 the title compound 421was obtained (189 mg, 56%) as white solid. MS (m/z): 424.4 (M+H).

Step 4:4-(2-(7-chloro-11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)ethoxy)-N-hydroxybenzamide(422)

Using Procedure B-3 (Table 5) with compound 421 the title compound 422was obtained (55 mg, 29%) as white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.04 (s, 1H), 8.90 (s, 1H), 7.74-7.71 (m, 2H), 7.68 (d, J=8.8 Hz, 2H),7.61-7.57 (m, 2H), 7.39-7.36 (m, 2H), 7.32 (td, J=7.4, 1.2 Hz, 1H), 6.91(d, J=8.8 Hz, 2H), 4.42 (br s, 2H), 4.30 (t, J=5.2 Hz, 2H). MS (m/z):447.4 (M+Na).

Example 222 Compound (429) Step 1: Compound (423)

The fluoric acid-pyridine (70%, 20 mL) was combined with ether (20 mL)(in a plastic vessel) and the mixture was cooled to 0° C. TheN-bromosuccinimide (2.5 g, 14 mmol) was added followed by5-dibenzosuberenone 2.06 g, 10 mmol). The reaction mixture was stirredat 15-20° C. for about 5 hours then poor over ice-water (100 mL)mixture. The aqueous layer was washed with water, saturated aqueoussolution of bicarbonate (until it stay basic), water and brine. Theorganic layer was let evaporated on the bench overnight. The needle thatformed were filtered and washed with a bit of ether to afford titlecompound 423 (2.06 g, 69%) as beige solid.

Step 2: Compound (424)

Title compound 423 (2.0 g, 6.6 mmol) was dissolved in toluene (20 mL)and dichloromethane (2 mL) and the mixture was cooled to 0° C. The DBUwas added and the reaction mixture was stirred at room temperature for 2hours. The mixture was diluted with ethyl acetate. The organic layer waswashed with 1N HCl (2 times), water and brine, dried over sodiumsulfate, filtered and evaporated to afford title compound 424 (1.3 g,88%) as a white solid. MS (m/z): 285.2 (M+H).

Step 3: Compound (425)

Title compound 424 (3.60 g, 12.63 mmol) was dissolved in DMSO (50 mL)and cesium fluoride (13.43 g, 88.38 mmol) was added. The reactionmixture was stirred at 135° C. for 5 hours. The mixture was poored overwater and extracted with ether. The combined organic layers were washedwith water and brine, dried over sodium sulfate, filtered andevaporated. The crude was purified by flash chromatography (0% to 20%ethyl acetate in hexanes) to afford title compound 425 (260 mg, 9%).

Step 4: Compound (426)

Using Procedure K-3 (Table 5) with compound 425 the title compound 426was obtained and used crude for next step.

Step 5: Compound (427)

Using Procedure M-3 (Table 5) with compound 426 the title compound 427was obtained (300 mg, 85% for 2 steps). MS (m/z): 209.1 (M-NH₂).

Step 6: Compound (428)

Using Procedure Y-3 (Table 5) with compound 427 the title compound 428was obtained (200 mg, 63%). ¹H NMR (CDCl₃) δ (ppm): 8.86-8.68 (m, 2H),7.78-7.29 (m, 8H), 6.93 (d, J=20.3 Hz, 1H), 6.45-6.43 (m, 2H), 4.31 (q,J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H).

Step 7: Compound (429)

Using Procedure B-3 (Table 5) with compound 428 the title compound 429was obtained (121 mg, 49%) as white solid. ¹H NMR (DMSO-d₆) δ (ppm):9.46 (s, 0.1H), 8.58 (br s, 2H), 7.80 (d, J=7.8 HZ, 1H), 7.73 (d, J=7.8Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.43 (d, J=7.6Hz, 1H), 7.39 (t, J=7.6 Hz, 2H), 7.27 (d, J=7.4 Hz, 1H), 7.21 (d, J=21.7Hz, 1H), 5.92 (s, 1H). MS (m/z): 361.4 (M−H).

Example 223N-hydroxy-4-(2-(5-oxobenzo[b]pyrido[3,2-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(433) Step 1:N-hydroxy-4-(2-(5-oxobenzo[b]pyrido[3,2-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(430)

Using Procedure S-3 (Table 5) with compound 2-chloronicotinoyl chlorideand 2-aminophenol the title compound 430 was obtained (3.69 g, 81%). MS(m/z): 249.2 (M+H).

Step 2: benzo[b]pyrido[3,2-f][1,4]oxazepin-5(6H)-one (431)

Title compound 430 (3.65 g, 14.7 mmol) was dissolved in DMF (25.0 mL)and sodium hydroxide powder (0.706 g, 17.7 mmol) was added. The reactionmixture was stirred at 130° C. for 5 hours. The mixture was cooled downto room temperature and ice cooled water was added. The precipitate wasfiltered. The solid was triturated in ethanol to afford title compound431 (1.798 g, 58%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.75 (s,1H), 8.50 (dd, J=4.8, 2.1 Hz, 1H), 8.27 (dd, J=7.6, 2.0 Hz, 1H), 7.46(dd, J=7.5, 4.8 Hz, 1H), 7.34 (dd, J=7.8, 1.2 Hz, 1H), 7.25-7.14 (m,3H). MS (m/z): 213.2 (M+H).

Step 3: methyl4-(2-(5-oxobenzo[b]pyrido[3,2-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzoate(432)

Using Procedure H-3 (Table 5) with compound 431 the title compound 432was obtained (0.360 g, 92%). MS (m/z): 391.3 (M+H).

Step 4:N-hydroxy-4-(2-(5-oxobenzo[b]pyrido[3,2-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(433)

Using Procedure B-3 (Table 5) with compound 432 the title compound 433was obtained (27 mg, 8%). ¹H NMR (DMSO-d₆) δ (ppm): 11.05 (s, 1H), 8.90(s, 1H), 8.46 (dd, J=4.8, 2.0 Hz, 1H), 8.23 (dd, J=7.6, 1.6 Hz, 1H),7.72 (dd, J=8.0, 1.6 Hz, 1H), 7.67 (d, J=9.2 Hz, 2H), 7.44 (dd, J=7.6,4.4 Hz, 1H), 7.39-7.25 (m, 3H), 6.90 (d, J=9.2 Hz, 2H), 4.47 (m, 2H),4.32 (t, J=5.2 Hz, 2H). MS (m/z): 392.3 (M+H).

Example 224N-hydroxy-4-(3-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)prop-1-ynyl)benzamide(436) Step 1: 10-(prop-2-ynyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one(434)

Using Procedure H-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-oneand 3-bromoprop-1-yne the title compound 85 was obtained (1.58 g, 89%)as an off-white solid. ¹H NMR (DMSO-d₆) δ (ppm): 7.76 (ddd, J=7.5, 1.7,0.4 Hz, 1H), 7.65 (dd, J=8.0, 1.7 Hz, 1H), 7.61 (ddd, J=8.2, 7.2, 1.8Hz, 1H), 7.41 (dd, J=7.8, 1.6 Hz, 1H), 7.37 (ddd, J=8.2, 1.0, 0.4 Hz,1H), 7.34-7.24 (m, 3H), 4.83 (d, J=2.3 Hz, 2H), 3.31 (t, J=2.3 Hz, 1H).MS (m/z): 250.0 (M+H)

Step 2: methyl4-(3-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)prop-1-ynyl)benzoate(435)

The title compound 434 (0.310 g, 1.24 mmol) and the methyl4-iodobenzoate (0.390 g, 1.48 mmol) were stirred in acetonitrile (10.0mL). Copper iodide (24 mg, 0.124 mmol) anddichlorobis(triphenylphosphine)palladium (87 mg, 0.124 mmol) were addedfollowed by triethylamine (0.44 mL, 3.11 mmol). The reaction mixture wasstirred at room temperature for 4 hours. The mixture was poor into ethylacetate and the organic layer was washed with water and brine, driedover sodium sulfate, filtered and evaporated. The crude was purified byflash chromatography (10-30% ethyl acetate in hexanes) to afford titlecompound 435 (285 mg, 60%) as a light brown solid. MS (m/z): 384.3(M+H).

Step 3:N-hydroxy-4-(3-(11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)prop-1-ynyl)benzamide(436)

Using Procedure B-3 (Table 5) with compound 435 the title compound 436was obtained (185 mg, 66%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.30 (s, 1H), 9.11 (s, 1H), 7.79 (dd, J=8.0, 1.6 Hz, 1H), 7.74-7.72 (m,3H), 7.64-7.59 (m, 1H), 7.47-7.26 (m, 7H), 5.11 (s, 2H) LRMS (ESI):(calc) 384.11 (found) 385.16 (MH)+

Example 2254-(2-(2-fluoro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)-N-hydroxybenzamide(441) Step 1: methyl 5-fluoro-2-(2-nitrophenoxy)benzoate (437)

Using the procedure described in Scheme 71, step 1, with methyl5-fluoro-2-hydroxybenzoate and 1-fluoro-2-nitrobenzene the titlecompound 437 was obtained (3.49 g, 84%) as a white solid. ¹H NMR(DMSO-d₆) δ (ppm): 8.06 (dd, J=8.1, 1.7 Hz, 1H), 7.74 (dd, J=8.8, 3.3Hz, 1H), 7.63-7.58 (m, 2H), 7.38 (dd, J=9.0, 4.5 Hz, 1H), 7.29 (ddd,J=8.3, 7.3, 1.1 Hz, 1H), 6.88 (dd, J=8.5, 1.0 Hz, 1H), 3.67 (s, 3H). MS(m/z): 292.2 (M+H).

Steps 2 and 3: 2-fluorodibenzo[b,f][1,4]oxazepin-11(10H)-one (438 and439)

Title compound 437 (3.48 g, 11.9 mmol) was dissolved in ethanol (30.0mL), acetic acid (1.0 mL) and THF (10 mL). The palladium on charcoal wasadded and the reaction mixture was stirred under 1 atmosphere ofhydrogen during 20 hours. The catalyst was filtered and the filtrate wasevaporated. The residue was diluted in ether and the organic layer waswashed with sodium bicarbonate saturated solution, water and brine thenconcentrated to afford title compound 438 (2.95 g, 95%) as a beigesolid. MS (m/z): 262.3 (M+H).

The solid 438 (1.51 g, 5.78 mmol) was dissolved in dichloromethane (20.0mL) and the mixture was cooled to 0° C. The trimethylaluminium (2M intol., 3.2 mL, 6.38 mmol) was added drop wise. The reaction mixture wasallowed to warm to room temperature then heated to 45° C. for 48 hours.The mixture was cooled down to room temperature and some water was addedslowly. This mixture was diluted with dichloromethane. This organiclayer was washed with 10% HCl (2 times), water and saturated aqueoussolution of sodium bicarbonate, dried over sodium sulfate, filtered andevaporated. The crude was triturated in 30% ethyl acetate in hexanes toafford title compound 439 (1.05 g, 79%) as a white solid. ¹H NMR(DMSO-d₆) δ (ppm): 10.68 (s, 1H), 7.51-7.46 (m, 2H), 7.44-7.39 (m, 1H),7.34 (ddd, J=7.6, 1.5, 0.6 Hz, 1H), 7.22-7.12 (m, 3H). MS (m/z): 230.1(M+H).

Step 4: methyl4-(2-(2-fluoro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzoate(440)

Using Procedure H-3 (Table 5) with compound 439 the title compound 440was obtained (0.344 g, 64%) as a white foam. MS (m/z): 408.3 (M+H).

Step 5:4-(2-(2-fluoro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)-N-hydroxybenzamide(441)

Using Procedure B-3 (Table 5) with compound 440 the title compound 441was obtained (210 mg, 62%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.05 (s, 1H), 8.90 (s, 1H), 7.70-7.65 (m, 3H), 7.49-7.38 (m, 4H),7.33-7.23 (m, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.45 (br s, 2H), 4.31 (t,J=5.2 Hz, 2H). MS (m/z): 409.3 (M+H).

Example 226N-hydroxy-4-(2-(5-oxo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethoxy)benzamide(444) Step 1: 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (442)

The chroman-4-one (5.0 g, 33.8 mmol) was dissolved in sulfuric acid (10mL) and the mixture was cooled at 0 oC. Sodium azide (2.88 g, 44.3 mmol)was added portionwise followed by some sulfuric acid (5 mL). Thereaction mixture was stirred at room temperature over night. The mixturewas then pour into ice-water and basified to pH=7 with potassiumhydroxide pellets. This aqueous layer was extracted with ether (twice).

The combined organic layer was washed with water and brine, dried overmagnesium sulfate, filtered and evaporated. The crude was purified byflash chromatography (50% to 100% ethyl acetate in hexanes) to affordtitle compound 442 (2.47 g, 45%) as a white solid. ¹H NMR (DMSO-d6) δ(ppm): 8.33 (s, 1H), 7.76 (dd, J=7.8, 2.0 Hz, 1H), 7.45 (ddd, J=7.6,7.2, 2.0 Hz, 1H), 7.12 (ddd, J=7.8, 7.2, 1.2 Hz, 1H), 7.01 (dd, J=8.3,1.1 Hz, 1H), 4.27 (dd, J=5.4, 4.4 Hz, 2H), 3.30 (dd, J=9.5, 5.5 Hz, 2H).MS (m/z): 164.0 (M+H).

Step 2: methyl4-(2-(5-oxo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethoxy benzoate(443)

Using Procedure H-3 (Table 5) with compound 442 the title compound 443was obtained (300 mg, 59%) as a white solid. MS (m/z): 342.3 (M+H).

Step 3:N-hydroxy-4-(2-(5-oxo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)ethoxy)benzamide(444)

Using Procedure B-3 (Table 5) with compound 443 the title compound 444was obtained (256 mg, 87%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):1.08 (s, 1H), 8.92 (s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.64 (dd, J=7.6, 1.6Hz, 1H), 7.48-7.44 (m, 1H), 7.16 (td, J=7.6, 1.2 Hz, 1H), 7.05-7.01 (m,3H), 4.36 (t, J=4.7 Hz, 2H), 4.23 (t, J=5.7 Hz, 2H), 3.92 (t, J=5.5 Hz,2H), 3.64 (t, J=5.1 Hz, 2H). MS (m/z): 343.2 (M+H).

Example 227N-hydroxy-4-(2-(5-oxobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(449) Step 1: N-(2-(benzyloxy)phenyl)-3-fluoroisonicotinamide (445)

Using Procedure S-3 (Table 5) with 3-fluoroisonicotinic acid and2-(benzyloxy)aniline the title compound 96 was obtained (4.01 g, 88%) asa white solid. MS (m/z): 323.2 (M+H).

Step 2: 3-fluoro-N-(2-hydroxyphenyl)isonicotinamide (446)

Title compound 445 (1.99 g, 6.18 mmol) was dissolved in the solution ofHBr (33% in AcOH, 15.0 mL) and acetic acid (10.0 mL). The reactionmixture was stirred at room temperature for 4 hours. The mixture wasdiluted with water and basified with solid sodium bicarbonate untilalkaline. More water was added to dissolve the salt and the aqueouslayer was extracted with ethyl acetate (twice). The combined organiclayers were washed with water and brine, dried over sodium sulfate,filtered and evaporated. The residue was triturated in 30% ethyl acetatein hexanes to afford title compound 446 (1.21 g, 84%) as a beige-yellowsolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.02 (s, 1H), 9.75 (s, 1H), 8.75 (d,J=2.0 Hz, 1H), 8.59 (dd, J=4.8, 1.3 Hz, 1H), 7.94 (dd, J=8.0, 1.6 Hz,1H), 7.76 (dd, J=6.1, 4.9 Hz, 1H), 7.03 (ddd, J=8.0, 7.4, 1.6 Hz, 1H),6.92 (dd, J=8.0, 1.4 Hz, 1H), 6.84 (td, J=7.6, 1.3 Hz, 1H). MS (m/z):233.2 (M+H).

Step 3: benzo[b]pyrido[4,3-f][1,4]oxazepin-5(6H)-one (447)

Using Procedure AG-3 (Table 5) with compound 446 the title compound 447was obtained (940 mg, 93%) as beige solid. MS (m/z): 213.1 (M+H).

Step 4: methyl4-(2-(5-oxobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzoate(448)

Using Procedure H-3 (Table 5) with compound 447 the title compound 448was obtained (530 mg, 63%) as a white solid. MS (m/z): 391.3 (M+H).

Step 5:N-hydroxy-4-(2-(5-oxobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(449)

Using Procedure B-3 (Table 5) with compound 448 the title compound 449was obtained (35 mg, 26%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.06 (s, 1H), 8.92 (s, 1H), 8.71 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.72(dd, J=8.4, 1.8 Hz, 1H), 7.69-7.66 (m, 3H), 7.44 (dd, J=8.0, 1.8 Hz,1H), 7.35-7.26 (m, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.48-4.47 (m, 2H), 4.32(t, J=5.4 Hz, 2H). MS (m/z): 392.3 (M+H).

Example 228 methyl3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoate(451) Step 1: methyl3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoate(450)

Methyl 3-bromopropanoate (0.227 g, 1.37 mmol) was dissolved in asolution of sodium azide in DMSO (0.5M, 2.7 mL, 1.37 mmol). The reactionmixture was stirred at room temperature for 3 hours. Water (3.0 mL),followed by sodium ascorbate (0.027 g, 0.137 mmol), followed by compound434 (0.340 g, 1.37 mmol), followed by copper sulfate (1M, 0.27 mL, 0.274mmol) were added. The reaction mixture was stirred at room temperaturefor 3 hours. The gummy solid formed was dissolved in a minimum of DCMand the mixture was pour into ethyl acetate (150 mL). The organic layerwas washed with water (2 times) and brine, dried over sodium sulfate,filtered and evaporated. The crude was purified by flash chromatography(100% ethyl acetate) to afford title compound 450 (160 mg, 31%) as acolorless oil. MS (m/z): 379.3 (M+H).

Step 2: methyl3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)propanoate(451)

Using Procedure B-3 (Table 5) with compound 450 the title compound 451was obtained (44 mg, 28%) as a white solid. ¹H NMR (CD₃OD) δ (ppm): 7.97(s, 1H), 7.79 (dd, J=8.4, 1.8 Hz, 1H), 7.68-7.65 (m, 1H), 7.56-7.52 (m,1H), 7.32-7.20 (m, 5H), 5.28 (s, 2H), 4.69 (t, J=6.8 Hz, 2H), 2.71 (t,J=6.8 Hz, 2H). MS (m/z): 380.3 (M+H).

Example 229N-hydroxy-4-(2-(2-methyl-5-oxo-1,2,3,4-tetrahydrobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(453) Step 1: methyl4-(2-(2-methyl-5-oxo-1,2,3,4-tetrahydrobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzoate(452)

Title compound 448 (0.249 g, 0.638 mmol) was solubilized in acetone(15.0 mL) and the methyl iodide (2.0 mL) was added. The reaction mixturewas stirred in a sealed tube at 60° C. for 18 hours. The mixture wascooled down and evaporated. The residue was dissolved in methanol (15mL) and Pt black (55 mg) was added. The reaction mixture was stirredover 55PSI of hydrogen for 3 hours. The catalyst was filtered and thefiltrate was evaporated. The crude was purified by flash chromatography(75-100% ethyl acetate in hexanes with 1.5% of ammonium hydroxide) toafford title compound 452 (133 mg, 51%). ¹H NMR (DMSO-d₆) δ (ppm): 7.89(d, J=8.2 Hz, 2H), 7.54 (d, J=8.0 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.19(t, J=7.7 Hz, 1H), 7.07 (dd, J=7.4, 1.2 Hz, 1H), 6.88 (d, J=8.2 Hz, 2H),4.38 (t, J=4.9 Hz, 2H), 4.31 (t, J=4.9 Hz, 2H), 3.84 (s, 3H), 3.17 (s,2H), 2.52-2.51 (m, 2H), 2.44 (m, 2H), 2.36 (s, 3H). MS (m/z): 409.4(M+H).

Step 2:N-hydroxy-4-(2-(2-methyl-5-oxo-1,2,3,4-tetrahydrobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(453)

Using Procedure B-3 (Table 5) with compound 452 the title compound 453was obtained (45 mg, 36%) as a white solid. ¹H NMR (CD₃OD) δ (ppm): 7.65(d, J=8.8 Hz, 2H), 7.55 (dd, J=8.0, 1.2 Hz, 1H), 7.27 (td, J=7.6, 1.6Hz, 1H), 7.20 (td, J=8.0, 1.6 Hz, 1H), 7.10 (dd, J=8.0, 1.6 Hz, 1H),6.87 (d, J=8.8 Hz, 2H), 4.38 (t, J=5.2 Hz, 2H), 4.30 (t, J=5.2 Hz, 2H),3.34-3.33 (m, 2H), 2.68 (t, J=5.8 Hz, 2H), 2.48 (br s, 5H). MS (m/z):410.4 (M+H).

Example 2304-(2-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-2-oxoethoxy)-N-hydroxybenzamide(457) Step 1: 1011-dihydrodibenzo[b,f][1,4]oxazepine (454)

Using Procedure Z-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-onethe title compound 454 was obtained (2.075 g, 100%) as beige solid. ¹HNMR (CD₃OD) δ (ppm): 7.29-7.19 (m, 2H), 7.16-7.04 (m, 2H), 7.01-6.99 (m,1H), 6.82-6.78 (m, 1H), 6.63-6.59 (m, 2H), 4.88 (s, 1H), 4.39 (s, 2H).MS (m/z): 198.1 (M+H).

Step 2: 2-bromo-1-(dibenzo[b,f][1,4]oxazepin-10(1H)-yl)ethanone (455)

Using Procedure S-3 (Table 5) with compound 454 the title compound 455was obtained (900 mg, 88%) as brown oil. MS (m/z): 318.1 (M+H).

Step 3: methyl4-(2-(dibenzo[b,f][1,4]oxazepin-10(1H)-yl)-2-oxoethoxy)benzoate (456)

Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate(0.512 g, 3.37 mmol) were dissolved in acetonitile (10.0 mL) and thecesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture wasstirred at 100° C. in a sealed tube for 4 hours. The mixture was cooleddown to room temperature and diluted with ethyl acetate. The organiclayer was washed with water (2 times) and brine, dried over sodiumsulfate, filtered and evaporated. The crude was purified by flashchromatography (30-40% ethyl acetate in hexanes) to afford titlecompound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).

Step 4:4-(2-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-2-oxoethoxy)-N-hydroxybenzamide(457)

Using Procedure B-3 (Table 5) with compound 456 the title compound 457was obtained (305 mg, 89%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.03 (s, 1H), 8.90 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.8 Hz,2H), 7.47-7.41 (m, 2H), 7.30-7.22 (m, 4H), 7.10-7.06 (m, 1H), 6.75 (d,J=8.8 Hz, 2H), 5.01-4.66 (m, 4H). MS (m/z): 391.1 (M+H).

Example 231 Compound (460) Step 1: Compound (458)

To a suspension of ammonium chloride (0.976 g, 18.242 mmol) in toluene(2.5 mL) was added trimethylaluminium (2M in toluene, 9.1 mL, 18.242mmol). This mixture was stirred for 1 hour and then added to a solutionof the cyano compound (2.000 g, 9.121 mmol) in toluene (2.5 mL). Thereaction mixture was heated at 80° C. for 3 hours. The mixture wascooled down to room temperature and poured into a suspension of SiO₂ inchloroform. The mixture was stirred for 5 minutes, filtered and washedwith methanol (100 mL). The filtrate was evaporated to afford titlecompound 458 (2.3 g, 100%) as beige solid. MS (m/z): 236.2 (M+2H).

Step 2: Compound (459)

Title compound 458 (0.500 g, 1.833 mmol), sodium(Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (0.418 g, 2.108mmol) and dimethylformamide (4 mL) were combined and stirred at 100° C.for 1 hour. Water was added and the precipitate was filtered. The solidwas purified by flash chromatography (0-30% ethyl acetate in hexanes) toafford title compound 459 (200 mg, 34%) as a white solid. ¹H NMR (CDCl₃)δ (ppm): 8.77 (s, 2H), 7.51-7.36 (m, 8H), 6.92 (s, 2H), 3.83 (s, 3H). MS(m/z): 330.2 (M+H).

Step 3: Compound (460)

Using Procedure B-3 (Table 5) with compound 459 the title compound 460was obtained (240 mg, 136%,) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.06 (s, 1H), 9.06 (s, 1H), 8.59 (s, 2H), 7.58-7.47 (m, 6H), 7.40-7.31(m, 2H), 7.01 (s, 2H).

Example 232N-hydroxy-3-(2-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzamide(464) Step 1:10-(2-(tert-butyldimethylsilyloxy)ethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one(461)

Using Procedure H-3 (Table 5) with dibenzo[b,f][1,4]oxazepin-11(10H)-oneand (2-bromoethoxy)(tert-butyl)dimethylsilane the title compound 461 wasobtained (4.35 g, 100%) as a colorless oil. MS (m/z): 370.4 (M+H).

Step 2: 10-(2-hydroxyethyl)dibenzo[b,f][1,4]oxazepin-11(10H)-one (462)

Title compound 461 (4.29 g, 11.6 mmol) was dissolved in THF (30.0 mL)and tetrabutylammonium fluoride (1M in THF, 13.4 mL, 13.4 mmol) wasadded. The reaction mixture was stirred at room temperature for 1 hour.The mixture was evaporated to ⅓ of the volume and then poured in ether.The organic layer was washed with water and brine, dried over sodiumsulfate, filtered and evaporated. The crude was purified by flashchromatography (50-70% ethyl acetate in hexanes) to afford titlecompound 462 (2.51 g, 85%) as a white solid. MS (m/z): 256.1 (M+H).

Step 3: methyl3-(2-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzoate (463)

Title compound 462 (0.300 g, 1.18 mmol), methyl 3-hydroxybenzoate (0.179g, 1.18 mmol) and triphenylphosphine (0.401 g, 1.53 mmol) were dissolvedin THF (5 mL) then diethylazodicarboxylate (0.222 mL, 1.41 mmol) wasadded. The reaction mixture was stirred at room temperature for 3 hours.The solvent was evaporated to provide title compound 463.

Step 4:N-hydroxy-3-(2-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzamide(464)

Using Procedure B-3 (Table 5) with compound 463 the title compound 464was obtained (18 gm, 11%) as a white solid. ¹H NMR (CD₃OD) δ (ppm): 7.77(dd, J=8.0, 1.8 Hz, 1H), 7.67 (dd, J=7.8, 1.8 Hz, 1H), 7.58-7.53 (m,1H), 7.38-7.22 (m, 8H), 7.09-7.04 (m, 1H), 4.59-4.51 (br s, 2H), 4.42(t, J=5.3 Hz, 2H). MS (m/z): 389.2 (M−H).

Example 233N-hydroxy-4-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)benzamide (466)Step 1: ethyl 4-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)benzoate(465)

To a suspension of dibenzo[b,f][1,4]oxazepin-11(10H)-one (0.623 g, 2.95mmol) in THF (10.0 mL), dichloromethane (10.0 mL) and triethylamine (2.0mL, 14.7 mmol) was added diacetoxycopper (0.587 g, 3.25 mmol) followedby 4-(ethoxycarbonyl)phenylboronic acid (1.15 g, 5.91 mmol). Thereaction mixture was stirred at room temperature for 5 days. It wasdiluted with ethyl acetate and this organic layer was washed with 10%HCl (2 times), water and brine, dried over sodium sulfate, filtered andevaporated. The crude was purified by flash chromatography (a 1^(st) onewith 20% ethyl acetate in hexanes and second one with 0.5% methanol indichloromethane) to afford title compound 465 (248 mg, 23%) as a whitesolid. MS (m/z): 360.3 (M+H).

Step 2:N-hydroxy-4-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)benzamide (466)

Using Procedure B-3 (Table 5) with compound 465 the title compound 466was obtained (40 mg, 17%) as a pink solid. ¹H NMR (DMSO-d₆) δ (ppm):11.33 (s, 1H), 9.14 (s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.81 (dd, J=8.0,2.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.51-7.43 (m, 4H), 7.36 (td, J=7.8, 0.8Hz, 1H), 7.22 (td, J=7.4, 1.6 Hz, 1H), 7.11 (td, J=7.8, 1.6 Hz, 1H),6.76 (dd, J=8.0, 1.6 Hz, 1H). MS (m/z): 347.2 (M+H).

Example 234(Z)-N-hydroxy-4-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide(470) Step 1: 1-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(467)

1-Methyl-1H-benzo[d][1,3]oxazine-2,4-dione (11.0 g, 62.1 mmol) and2-aminoacetic acid (5.13 g, 68.3 mmol) were dissolved in DME (60 mL) andwater (20 mL) and triethylamine was added. The reaction mixture wasstirred at 60° C. for 4 hours. The mixture was concentrated in vacuo toget a light tan heavy oily residue that was dissolved in acetic acid (75mL). This mixture was refluxed 4 hours then cooled down to roomtemperature. The solvent was evaporated to get a tan heavy oil. The oilwas allowed to stand at room temperature overnight in ether (50 mL). Thebeige crystalline solid was filtered and washed with ether. The solidwas then triturated in ether to afford title compound 467 (7.95 g, 67%)as a beige crystalline solid. ¹H NMR (DMSO-d₆) δ (ppm): 8.70 (s, 1H),7.70 (d, J=7.6 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H),7.32 (t, J=7.5 Hz, 1H), 3.75-3.72 (m, 1H), 3.51-3.46 (m, 1H), 3.28 (s,3H). MS (ESI): 190.90 (MH)+

Step 2: (E)-5-chloro-1-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one (468)

The title compound 467 (1.54 g, 8.10 mmol) was heated in phosphorusoxychloride (15 mL) at 95° C. for 2 hours. The reaction mixture was thencooled to room temperature and excess of phosphorus oxychloride wasremoved under reduced pressure. The black oil was dissolved in ethylacetate and the organic phase was washed with sodium bicarbonate(saturated solution) and brine, dried over sodium sulfate, filtered andconcentrated to afford crude title compound 468 that was used as suchfor the next step. MS (ESI): 209.12 (MH)+.

Step 3: (Z)-ethyl4-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzoate(469)

Title compound 468 (1.69 g, 8.10 mmol) was dissolve in DME (50 mL) and4-(methoxycarbonyl)phenylboronic acid (1.47 g, 7.58 mmol) was addedfollowed by tetrakis(triphenylphosphine) palladium (0) (0.301 g, 0.260mmol) and then sodium carbonate (2M in water, 12 mL, 24.00 mmol). Thereaction mixture was stirred at 90° C. for 1 h, cooled at roomtemperature and poured into ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulfate, filtered andconcentrated. The crude was purified by flash chromatography (10% ethylacetate in hexanes) to afford title compound 469 (1.41 g, 54%) as a redfoam. MS (ESI): 323.42 (MH)+.

Step 4:(Z)-N-hydroxy-4-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide(470)

Using Procedure B-3 (Table 5) with compound 469 the title compound 470was obtained (323 mg, 24%) as a pink solid. ¹H NMR (DMSO-d₆) δ (ppm):11.33 (s, 1H), 9.12 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.69-7.65 (m, 1H),7.62-7.58 (m, 3H), 7.31-7.23 (m, 2H), 4.59 (d, J=10.4 Hz, 1H), 3.76 (d,J=10.4 Hz, 1H), 3.32 (s, 3H). MS (m/z): 310.3 (M+H).

Example 235N-hydroxy-2-(3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxamide(475) Step 1: 2-chloro-3-hydrazinylpyrazine (471)

2,3-Dichloropyrazine (2 g, 13.42 mmol), hydrazine (1.324 g, 26.8 mmol)and ethanol (40 ml) were combined and the reaction mixture was stirredat 80° C. for 1.5 h. The mixture was cooled to room temperature and theyellow flakes were filtered off. The solid was washed with a smallamount of water and dried. The mother liquor was concentrated to afforda yellow solid triturated with a small amount of water and dried. The 2solids were combined to afford title product 471 (1.15 g, 59%) as yellowsolid. MS (m/z): 145.0 (M+H).

Step 2: 8-chloro-3-phenyl-[1,2,4]triazolo[4,3-a]pyrazine (472)

Title compound 471 (0.8 g, 5.53 mmol) and Trimethyl orthobenzoate (5 mL,29.1 mmol) were combined and the reaction mixture was stirred at 120° C.for 3 h. The mixture was cooled to room temperature and the solid wasfiltered and washed with hexanes to afford title compound 472 (1.35 g,100%) as a beige solid. MS (m/z): 231.1 (M+H)

Step 3: 3-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (473)

Title compound 472 (310 mg, 1.34 mmol) was dissolved in EtOH (25 mL) and10% Pd/C (75 mg, 25% w/w) was added. The reaction mixture was stirredunder 1 atmosphere of hydrogen over night. The catalyst was filtered andthe filtrate was evaporated to afford title compound 473 (269 mg, 100%).MS (m/z): 201.1 (M+H).

Step 4: ethyl2-(3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxylate(474)

Using Procedure Y-3 (Table 5) with compound 473 the title compound 474was obtained (85 mg, 18%) as a clear oil. MS (m/z): 353.5 (M+3).

Step 5:N-hydroxy-2-(3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxamide(475)

Using Procedure B-3 (Table 5) with compound 474 the title compound 475was obtained (85 mg, 93%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.19 (s, 1H), 9.09 (s, 1H), 8.79 (s, 2H), 7.78-7.77 (m, 2H), 7.76-7.75(m, 3H), 5.20-5.15 (m, 2H), 4.35-4.20 (m, 4H). MS (m/z): 338.4 (M+H).

Example 236N-hydroxy-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxamide(481) Step 1: 2-hydrazinylpyrazine (476)

Using Procedure AU-3 (Table 5) with 2-chloropyrazine the title compound476 was obtained (4.4 g, 46%) as a yellow solid. MS (m/z): 111.0 (M+H).

Step 2: 2,2,2-trifluoro-N′-(pyrazin-2-yl)acetohydrazide (477)

In a 100 ml RB, trifluoroacetic anhydride (15 mL, 106 mmol) was addedslowly to title compound 476 (1.7 g, 15.44 mmol) at 0° C. (exotherm).The mixture was stirred at room temperature for 2 h then concentrated togive compound 477 as a red paste that was used crude for next step (>3.5g).

Step 3: 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (478)

To title compound 477 (3.12 g, 15.14 mmol) was added PPA (15 mL). Themixture was heated to 150° C. for 1 h then poored over water. Theaqueous was basified with conc. NH₄OH (exotherm) at 0° C. Water wasadded until everything was dissolved. The mixture was extracted withethyl acetate (×4). The organics were washed with brine, died overNa₂SO₄, filtered and concentrated to a brown paste. The residue waspurified by flash chromatography (0% to 70% ethyl acetate in hexanes) toafford title compound 478 (0.9 g, 32%) as a brown solid. MS (m/z): 189.1(M+H).

Step 4:3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine(479)

Using Procedure G-3 (Table 5) with compound 478 the title compound 479(crude) was obtained (130 mg, 89%) as a brown oil. MS (m/z): 193.1(M+H).

Step 5: ethyl2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxylate(480)

Using Procedure Y-3 (Table 5) with compound 479 the title compound 480was obtained (550 mg, 49%) as a beige solid. MS (m/z): 343.4 (M+H).

Step 6:N-hydroxy-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrimidine-5-carboxamide(481)

Using Procedure B-3 (Table 5) with compound 480 the title compound 481was obtained (198 mg, 59%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):11.19 (s, 1H), 9.10 (s, 1H), 8.77 (s, 2H), 5.20 (s, 2H), 4.32 (t, J=5.1Hz, 2H), 4.25 (t, J=4.9 Hz, 2H). MS (m/z): 330.2 (M+H).

Example 2374-((6,11-dihydrodibenzo[b,e]oxepin-11-ylamino)methyl)-N-hydroxybenzamide(486) Step 1: dibenzo[b,e]oxepin-11(6H)-one (482)

The 2-(phenoxymethyl)benzoic acid (22.18 g, 97 mmol) was dissolved inDCM (200 mL) and trifluoroacetic anhydride (20.59 mL, 146 mmol) wasadded, followed by a catalytic amount of borontrifluoride etherate (2.22mL, 17.5 mmol). The reaction mixture was heated at 40° C. for 2 hours.The solution was then washed with water, sodium bicarbonate (saturatedsolution) and water. The organic phases was dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude product waspurified on silica gel (10-20% ethyl acetate in hexanes) to afford titlecompound 482 (19.937 g, 98%) as a light pink solid. MS (m/z): 211.1(M+H).

Step 2: (E)-dibenzo[b,e]oxepin-11(6H)-one oxime (483)

Using Procedure K-3 (Table 5) with compound 482 the title compound 483was obtained (4.458 g, 40%) as a white solid. MS (m/z): 226.2 (M+H).

Step 3: 6,11-dihydrodibenzo[b,e]oxepin-11-amine (484)

Using Procedure M-3 (Table 5) with compound 483 the title compound 484was obtained (2.87 g, 100%) as a yellow oil. MS (m/z): 212.2 (M+H).

Step 4: methyl4-((6,11-dihydrodibenzo[b,e]oxepin-11-ylamino)methyl)benzoate (485)

Using Procedure A-3 (Table 5) with compound 484 the title compound 485was obtained (1.436 g, 93%) as a yellow oil. ¹H NMR (DMSO-d₆) δ (ppm):7.89 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.37-7.14 (m, 5H),6.93-6.78 (m, 2H), 6.44 (d, J=12.3 Hz, 1H), 4.91 (d, J=12.1 Hz, 1H),4.65 (d, J=2.9 Hz, 1H), 3.83 (d, J=0.4 Hz, 3H), 3.69 (t, J=6.7 Hz, 2H),3.19-3.14 (m, 1H). MS (m/z): 360.4 (M+H).

Step 5:4-((6,11-dihydrodibenzo[b,e]oxepin-11-ylamino)methyl)-N-hydroxybenzamide(486)

Using Procedure B-3 (Table 5) with compound 485 the title compound 486was obtained (56 mg, 4%) as a light pink solid. ¹H NMR (DMSO-d₆) δ(ppm): 11.14 (s, 1H), 8.99 (s, 1H), 7.70-7.68 (d, J=7.6 Hz, 2H),7.38-7.23 (m, 6H), 7.18-7.14 (m, 2H), 6.87 (t, J=7.0 Hz, 1H), 6.78 (d,J=7.6 Hz, 1H), 6.44 (d, J=12.4 Hz, 1H), 4.91 (d, J=12.4 Hz, 1H), 4.65(d, J=2.8 Hz, 1H), 3.63 (d, J=5.6 Hz, 2H), 3.07 (br s, 1H). MS (m/z):361.4 (M+H).

Example 2382-((1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-hydroxypyrimidine-5-carboxamide(490) Step 1:((1S,2R)-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclopropyl)methanol(487)

To a solution of 2-(3,4-Dichlorophenyl)acetonitrile (3.5 g, 18.81 mmol)and (S)-(+)-Epichlorohydrin (1.877 ml, 23.99 mmol) in tetrahydrofuran(18.5 mL) at −15° C. (dry ice/ethanol/water bath, internal tempmonitored with thermocouple) under atmosphere of N2 was added sodiumbis(trimethylsilyl)amide (16.5 mL, 33.0 mmol) dropwise over 3 hours. Thereaction mixture was stirred for additional 3 hours at −15° C., then,overnight at 4° C. (cold room). The mixture was cooled to −5° C. andborane-methyl sulfide complex (4.4 mL, 44.0 mmol) was added over 2 hoursvia syringe pump. The reaction mixture was then gradually warmed to 40°C. over 3 hours. After aging 1.5 hours at 40° C., the reaction mixturewas cooled to 20-25° C. and slowly quenched into a 2N HCl solution (27.7L). The quenched mixture was then stirred for 1 h at 40° C. Ammoniumhydroxide concentrated (6.3 L) was added and the aqueous layer wasdiscarded. i-PrOAc (18.5 L) and 5% dibasic sodium phosphate (18.5 L)were charged. The organic phase was then washed with saturated brine(18.5 L), dried over magnesium sulfate, filtered and evaporated toafford title compound 487 (4.63 g, 100%).

Step 2: (1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (488)

Title compound 487 (4.63 g, 18.81 mmol) was dissolved in isopropylacetate (24.5 mL). The above crude amino alcohol solution in isopropylacetate was slowly subsurface-added to a solution of thionyl chloride(1.61 ml, 22.06 mmol) in isopropyl acetate (17.5 mL) at ambienttemperature over 2 hours. After aging additional 1-5 h, 5.0 N sodiumhydroxide (16.4 mL) was added over 1 hour while the batch temperaturewas maintained at <30° C. with external cooling. The two-phase reactionmixture was stirred for 1 hour at ambient temperature to allow pH tostabilize (usually to 8.5-9.0) with sodium hydroxide pH titration. Theorganic phase was washed with 40% aqueous isopropanol (21 mL) followedby water (10.5 mL). Concentrated HCl (1.69 mL) was added. The aqueousisopropyl acetate was azeotropically concentrated in vacuum to ca. 24.5mL. Methylcyclohexane (17.5 mL) was added dropwise over 2 hours.Compound did not crystallize out. The pH was adjusted to neutral andorganic layer was separated. The organic layer was washed with water andbrine, dried over magnesium sulfate, filtered and evaporated. Theresidue was purified by ISCO (EtOAc to 60% MeOH in EtOAc, 40 g silicacolumn) to afford title compound 488 (1.8 g, 42%) as a thick yellow oil.¹H NMR (CD₃OD) δ (ppm): 7.44 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H),7.18 (dd, J=8.4, 2.2 Hz, 1H), 3.31-3.30 (m, 2H), 3.23-3.17 (m, 2H),1.97-1.93 (m, 1H), 1.20-1.04 (m, 2H). MS (m/z)=228.15 (M+H)

Step 3: ethyl2-((1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidine-5-carboxylate(489)

Using Procedure Y-3 (Table 5) with compound 488 the title compound 489was obtained (176 mg, 43%) as a yellow solid. MS (m/z): 378.5 (M+H).

Step 4:2-((1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-hydroxypyrimidine-5-carboxamide(490)

Using Procedure B-3 (Table 5) with compound 489 the title compound 490was obtained (132 mg, 78%) as a white solid. ¹H NMR (CD₃OD) δ (ppm):8.67 (s, 2H), 7.46 (m, 2H), 7.23 (dd, J=2.4 Hz, 8.4 Hz, 1H), 4.31 (d,J=11.2 Hz, 1H), 4.07 (d, J=11.2 Hz, 1H), 3.76 (d, J=11.2 Hz, 2H), 2.14(quin, J=4 Hz, 1H), 1.22 (m, 1H), 0.90 (t, J=4.8 Hz, 1H). MS (m/z):363.4 (M−H).

Example 239(Z)-4-(7-bromo-2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide(495) Step 1: methyl 4-(2-aminothiophene-3-carbonyl)benzoate (491)

Triethylamine (1.331 mL, 9.55 mmol) was added with stirring to asolution of methyl 4-(2-cyanoacetyl)benzoate (4.85 g, 23.87 mmol) and1,4-dithiane-2,5-diol (1.817 g, 11.93 mmol) in dimethylformamide (10mL), to give a yellow solution. After 15 min, the solution was heated to60° C. for 2 hours and stirred at room temperature overnight. Water (50mL), ethyl acetate (50 mL), and glacial acetic acid (ca. 1-3 mL) wereadded to the oily residue until the organic layer became clear. Afterseparation of the organic layer and further extraction of the aqueouslayer with ethyl acetate (50 mL), the combined organic layers werewashed subsequently with 5% aqueous NaHCO₃ and H₂O, dried over anhydrousMgSO₄. The solvent was removed and the residue was purified via ISCO(0-50% EtOAc/Hexanes; 80 g silica gel column) to afford title compound491 (3.7 g, 59%) as a yellow solid. MS (m/z): 357.4 (M+H).

Step 2: methyl 4-(2-(2-aminoacetamido)thiophene-3-carbonyl)benzoate(492)

In a 100 mL round-bottomed flask was dissolved title compound 491 (1 g,2.96 mmol) and sodium iodide (0.533 g, 3.55 mmol) in tetrahydrofuran (20mL) to give a yellow suspension. The mixture was heated at reflux for 2hours. The mixture was cooled to −78° C. A Dewar-type condenser wasattached and filled with dry ice/acetone. Ammonia was introduced as agas and about 30 mL was condensed into the flask. The reaction mixturewas left to warm up to room temperature over the weekend. The solventwas removed in vacuo and the residue was purified via ISCO (50-100%EtOAc/Hexanes; 40 g silica gel column) to obtain product as a tanpowder. The solid was purified by suspending it in 1:1dichloromethane/ether and filtering to afford title compound 492 (265mg, 28%) as a tan powder which was sufficiently pure for the next step.MS (m/z): 319.3 (M+H).

Step 3: (Z)-methyl4-(2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-5-yl)benzoate (493)

In a 75 mL pressure flask was suspended compound 492 (0.265 g, 0.832mmol) and acetic acid (0.071 mL, 1.249 mmol) in methanol (20 mL) to givea yellow suspension. The reaction mixture was heated at 100° C.overnight. The solvent was removed to afford title compound 493 (250 mg,100%) as a tan powder. MS (m/z): 301.3 (M+H).

Step 4: (Z)-methyl4-(7-bromo-2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-5-yl)benzoate(494)

In a 20 mL dram screw-cap vial with septum was dissolved compound 493(0.140 g, 0.466 mmol) in pyridine (3 mL) to give an orange solution. Themixture was cooled to 0° C. and bromine (0.029 mL, 0.559 mmol) was addeddropwise. The reaction mixture was left to stir at 0° C. for 1 hour. Themixture was quenched with saturated thiosulfate solution and extractedwith ethyl acetate. The organic layer was washed several times withwater, then brine, dried over magnesium sulfate, filtered andevaporated. The residue was suspended in ether and filtered to affordtitle compound 494 (101 mg, 57%) as a tan solid. MS (m/z): 379.33 (M+H).

Step 5:(Z)-4-(7-bromo-2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide(495)

Using Procedure B-3 (Table 5) with compound 494 the title compound 495was obtained (40 mg, 40%) as a tan solid. ¹H NMR (CD₃OD) δ (ppm): 7.84(d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 6.85 (s, 1H), 4.36 (s, 2H).MS (m/z): 378.2 (M−H).

Example 240 N-hydroxy-4-((2-phenyl-1H-indol-1-yl)methyl)benzamide (497)Step 1: 4-((2-phenyl-1H-indol-1-yl)methyl)benzoic acid (496)

Using Procedure H-3 (Table 5) with 2-phenyl-1H-indole and4-(bromomethyl)benzoic acid the title compound 496 was obtained (332 mg,22%) as a tan solid. ¹H NMR (DMSO-d₆) δ (ppm): 7.78 (d, J=8.2 Hz, 2H),7.61 (dd, J=7.0, 1.7 Hz, 1H), 7.50-7.41 (m, 5H), 7.34 (d, J=8.2 Hz, 1H),7.14-7.06 (m, 2H), 6.93 (d, J=8.2 Hz, 2H), 6.67 (d, J=0.8 Hz, 1H), 5.51(s, 2H). MS (m/z)=326.2 (M−H).

Step 2: N-hydroxy-4-((2-phenyl-1H-indol-1-yl)methyl)benzamide (497)

Title compound 496 (332 mg, 1.014 mmol), hydroxylamine hydrochloride (85mg, 1.217 mmol), BOP (583 mg, 1.318 mmol), triethylamine (0.424 mL, 3.04mmol) and pyridine (7 mL) were stirred together at room temperature for1 hour. All solvents were then removed under reduced pressure, and theresidue was diluted with ethyl acetate and brine. Following extractionwith ethyl acetate, the combined organic layers were dried withanhydrous sodium sulfate, filtered, and concentrated. The residue wasthen purified by column chromatography on silica gel using 50-100%EtOAc/hexanes as the eluent to afford title compound 497 (0.058 g, 17%)as a white solid. ¹H NMR (CD₃OD) δ (ppm): 7.66-7.62 (m, 3H), 7.50-7.38(m, 5H), 7.28-7.23 (m, 1H), 7.17-7.08 (m, 2H), 7.03 (d, J=8.4 Hz, 2H),6.65 (d, J=0.6 Hz, 1H), 5.51 (s, 2H). MS (m/z): 343.5 (M+H).

Example 241(S)-2-(2-(1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(502) Step 1: (S)-ethyl2-(2-(tert-butoxycarbonyl)pyrrolidin-1-yl)pyrimidine-5-carboxylate (498)

Using Procedure Y-3 (Table 5) with (S)-tert-butylpyrrolidine-2-carboxylate and ethyl2-(methylsulfonyl)pyrimidine-5-carboxylate the title compound 498 wasobtained (278 mg, 66%). MS (m/z): 322.3 (M+H).

Step 2: (S)-1-(5-(ethoxycarbonyl)pyrimidin-2-yl)pyrrolidine-2-carboxylicacid (499)

HCl in dioxane (3 mL) was added to compound 498 (278 mg, 0.865 mmol) andthe reaction mixture was stirred overnight. The reaction was thenconcentrated to afford compound 499 which was used without furtherpurification. MS (m/z): 266.2 (M+H).

Step 3: (S)-ethyl2-(2-(2-aminophenylcarbamoyl)pyrrolidin-1-yl)pyrimidine-5-carboxylate(500)

Using Procedure S-3 (Table 5) with compound 499 the title compound 500was obtained (117 mg, 51%).

Step 4: (S)-ethyl2-(2-(1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)pyrimidine-5-carboxylate(501)

AcOH (2 mL) was added to compound 500 (117 mg, 0.329 mmol) and thesolution was heated at 90° C. for 30 minutes. The solvent was evaporatedunder reduced pressure. The residue was then partitioned between ethylacetate and water and the pH adjusted to pH=10. The organic phase wasseparated, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in hexanes to afford titlecompound 501 (72 mg, 65%). MS (m/z): 338.4 (M+H).

Step 5:(S)-2-(2-(1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-N-hydroxypyrimidine-5-carboxamide(502)

Using Procedure B-3 (Table 5) with compound 501 the title compound 502was obtained (17 mg, 25%). ¹H NMR (CD₃OD) δ (ppm): 8.72 (bs, 1H), 8.50(bs, 1H), 7.46 (s, 2H), 7.17 (m, 2H), 5.48 (d, J=8.0 Hz, 1H), 4.04 (m,1H), 3.79 (m, 1H), 2.53 (m, 1H), 2.28 (m, 1H), 2.14 (m, 2H). MS (m/z):325.3 (M+H).

The general procedures A-3 to BC-3 used to synthesize compounds of thisinvention are described in the Table 5. A specific example of eachgeneral procedure is provided in the indicated step of a particularexample. It is realized that substrates and methods may be modifiedand/or adapted by those of skill in the art in order to facilitate thesynthesis of the compounds within the scope of the present invention.

TABLE 5 Proc Sc Ex Step Reaction Conditions A-3 50 200 1

B-3 50 200 2

C-3 51 201 1

D-3 52 202 1

E-3 52 202 2

F-3 53 203 1

G-3 54 204 1

H-3 55 205 2

I-3 56 206 1

J-3 56 206 2

K-3 57 207 1

L-3 57 207 2

M-3 58 208 1

N-3 59 209 1

O-3 59 209 2

P-3 59 209 4

Q-3 60 210 1

R-3 60 210 2

S-3 60 210 3

T-3 60 210 4

U-3 61 211 2

V-3 62 212 2

W-3 62 212 3

X-3 62 212 4

Y-3 64 214 1

Z-3 65 215 1

AA-3 65 215 2

AB-3 68 218 2

AC-3 69 219 1

AD-3 72 222 1

AE-3 72 222 2

AF-3 72 222 3

AG-3 73 223 2

AH-3 74 224 2

AI-3 76 226 1

AJ-3 77 227 2

AK-3 78 228 1

AL-3 79 229 1

AM-3 81 231 1

AN-3 81 231 2

AO-3 82 232 2

AP-3 82 232 3

AQ-3 83 233 1

AR-3 84 234 1

AS-3 84 234 2

AT-3 84 234 3

AU-3 85 235 1

AV-3 85 235 2

AW-3 86 236 2

AX-3 87 237 1

AY-3 88 238 1

AZ-3 88 238 2

BA-3 89 239 1

BB-3 89 239 4

BC-3 91 241 4

The examples described in Table 6 were prepared following thepreparative sequences (general procedures A-3 to BC-3) indicated inTable 5 or using a preparative sequence(s) already described (forexample, Table 1 and/or Table 3).

TABLE 6 Ex Cpd Structure Name Characterization 200 351

(Z)-4-((5H- dibenzo[b,f] azepin-5- yl)methyl)-N- hydroxybenzamide(DMS0-d6) δ (ppm): 11.06(s, 1H), 8.96(s, 1H), 7.57(d, J = 8.4 Hz, 2H),7.47(d, J = 8.4 Hz, 2H), 7.21(td, J = 1.6 and 7.2 Hz, 2H), 7.18-7.13(m,2H), 7.10(dd, J = 1.6 and 7.6 Hz, 2H), 6.6(td, J = 1.2 and 7.2 Hz, 2H),6.85(s, 2H), 5.00(s, 2H). LRMS: 342.1 (calc) 343.2 (found) 201 353

¹H NMR(DMSO-d₆) δ (ppm): 10.7-10.4 (1H , br s), 8.9-8.7 (1H, br s),7.44-7.25 (8H, m), 6.99 and 6.91 (2H, AB doublet, J = 12.1 Hz), 5.75(1H, s). MS (m/z): 264.0 (M + H). 202 356

ε-N-hydroxy-3- ((Z)-2-oxo-5- phenyl-2,3- dihydro-1H- benzo[e][1,4]diazepin-8- yl)acrylamide ¹H NMR(DMS0-d₆) δ (ppm)-formate salt: 10.54(s, 1H), 7.61-7.53 (m, 3H), 7.50-7.44 (m, 3H), 7.26-7.22 (m, 2H), 7.17(td, J = 7.2,1.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.12-4.01 (br s,2H). MS (m/z): 322.2 (M + H) 203 359

ε-N-hydroxy-3- ((Z)-1-methyl- 2-oxo-5-phenyl- 2,3-dihydro-1H-benzo[e][1,4] diazepin-8- yl)acrylamide ¹H NMR (CD₃OD) δ(ppm)-formate salt: 7.70-7.56 (m, 7H), 7.29 (d, J = 4.1 Hz, 2H), 6.55(d, J = 15.8 Hz, 1H), 4.63 (d, J = 10.8 Hz, 1H), 3.83 (d, J = 10.8 Hz,1H), 3.43 (s, 3H). MS (m/z): 336.1 (M + H). 204 361

(Z)-N-hydroxy-3- (1-methyl-2- oxo-5-phenyl-2,3- dihydro-1H-bcnzo[e][1,4] diazepin-8-yl) propanamide (MeOD) d(ppm): 7.68-7.63 (m,1H), 7.56 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.29-7.23 (m,4H), 4.58 (d, J = 11.0 Hz, 1H), 3.79 (d, J = 11.0 Hz, 1H), 3.42 (s, 3H),2.97 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.8 Hz, 2H). MS (m/z): 338.2 (M +H) 205 364

(Z)-N-hydroxy-6- (2-oxo-5-phenyl- 2,3-dihydro-1H- benzo[e][1,4]diazepin-1-yl) hexanamide (CD₃OD) δ (ppm): 7.69-7.61 (m, 2H), 7.55-7.49(m, 3H), 7.47-7.42 (m, 2H), 7.32-7.25 (m, 2H), 4.58 (d, J = 10.6 Hz,1H), 4.43-4.36 (m, 1H), 3.81 (d, J = 10.7 Hz, 1H), 3.78-3.71 (m, 1H),1.85 (t, J = 7.7 Hz, 2H), 1.56-1.37 (m, 4H), 1.16 -1.09 (m, 2H). MS(m/z): 366.1 (M + H). 206 367

(Z)-2-(5H-dibenzo [b,f]azepin-5-yl)-N- hydroxyacetamide (CDCl₃) δ (ppm):7.28 (2H, t, J = 7.1 Hz), 7.16-7.11 (4H, m), 7.04 (2H, t, J = 7.1Hz),6.83 (2H, s), 4.42 (2H, s). MS (m/z): 267.0 (M + H). 207 370

(CD₃OD) δ (ppm): 7.51 (dd, J = 7.8, 1.5 Hz, 1H), 7.30-7.25 (m, 4H),7.24-7.15 (m, 2H), 7.13 (d, J = 7.6 Hz, 1H), 4.13 (t, J = 6.5 Hz, 2H),3.12-3.00 (m, 4H), 2.06 (t, J = 7.5 Hz, 2H), 1.67-1.56 (m, 4H),1.40-1.20 (m, 6H). MS (m/z): 381.2 (M + H). 208 373

(MeOH-d₄) δ (ppm): 7.80 (d, J = 8.4 Hz, 2H), 7.53 (d, J =8.4 Hz, 2H),7.42-7.38 (m, 4H), 7.33-7.27 (m, 4H), 5.49 (br s, 1H), 4.20 (s, 2H),3.44-3.42 (m, 2H), 3.08 (m, 2H). MS (m/z): 359.1 (M + H). 209 379

ε-3-((Z)-5- (cyclopropyl- methyl)-5H- dibenzo[b,f]azepin- 2-yl)-N-hydroxyacrylamide (CD₃OD) δ (ppm): 7.5-7.4 (2H, m), 7.25- 7.2 (2H, m),7.05-7.0 (3H, m), 6.99-9.93 (1H, m), 6.75-6.65 (2H, observed 2d), 6.33(1H, d, J = 15.7 Hz), 3.57 (2H, d, J = 6.4 Hz), 1.05-0.95 (1H, m),0.45-0.37 (2H, m), 0.25-0.18 (2H, m). MS (m/z): 333.1 (M + H). 210 385

4-(11-cyclopropyl- 5-oxo-5H-benzo [b]pyrido[2,3- e][1,4]diazepin-6(HH)-yl)-N- hydroxybutanamide (CD₃OD) δ (ppm): 8.36 (1H, dd, J = 4.9,1.7 Hz), 8.00 (1H, dd, J = 7.6, 1.7 Hz), 7.52 (1H, dd, J = 8.1, 1.3 Hz),7.38 (1H, dd, J = 8.0, 1.1 Hz), 7.26(1H, td, J = 7.8, 1.3 Hz), 7.23-7.17(1H, td observed), 7.12 (1H, dd, J = 7.6, 4.9 Hz), 4.58-4.48 (1H, m),3.76-3.68 (1H, m), 3.60-3.55 (1H, m), 2.06 (2H, t, J = 7.6 Hz),1.95-1.80 (1H, m), 1.79-1.73 (1H, m), 1.05-0.87 (2H, m), 0.60-0.42 (2H,m). MS (m/z): 353.1 (M + H). 211 388

(CD₃OD) δ (ppm): 7.70-7.55 (3H, m), 7.47 (2H, d, J = 7.8 Hz), 7.42-7.34(4H, m), 7.33-7.21 (5H, m), 6.56 (1H, d, J = 15.9 Hz), 5.49 (1H, br s),4.16 (1H, br s), 3.50-3.36 (2H, m), 3.25-2.98 (2H, m). MS (m/z): 385.1(M + H). 212 393

(Z)-2-(4-((5H- dibenzo[b,f] azepin-5-yl) methyl)phenyl)-N-hydroxyacetamide (dmso) δ (ppm): 10.57 (1H, s), 8.74 (1H, s), 7.31(2H, d, J = 8.2 Hz), 7.19 (2H, td, J = 7.2, 1.6 Hz), 7.11 (2H, d, J =7.2 Hz), 7.10-7.04 (4H, m), 6.92 (2H, m), 6.81 (2H, s), 4.89 (2H, s),3.13 (2H, s). MS (m/z): 357.1 (M + H) 213 395

(DMSO-d₆) δ (ppm): 11.13 (1H, s), 8.94 (1H, s), 7.74 (2H, d, J = 8.8Hz), 7.67 (1H, d, J = 7.4 Hz), 7.42-7.34 (4H, m), 7.32-7.26 (2H, m),7.26-7.19 (3H, m), 3.21-2.99 (4H, m). MS (m/z): 359.0 (M + H). 214 397

¹H NMR (MeOD) δ (ppm): 8.62 (2H, s), 7.44 (2H, d, J = 7.1 Hz), 7.17-7.09(6H, m), 6.66 (1H, s), 3.38-3.30 (2H, m), 3.28-3.18 (2H, m). MS (m/z):345.1 (M − H). 215 400

7-(dibenzo[b,f] [1,4]oxazepin- 10(11H)-yl)-N- hydroxyheptanamide ¹H NMR(400 MHz, CD₃OD) δ (ppm): 7.71 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H),7.52-7.48 (m, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.39-7.36 (m, 2H), 7.27 (t,J = 7.4 Hz, 1H), 5.01 (s, 2H), 3.56 (t, J = 8.0 Hz, 2H), 2.15 (br s,2H), 1.73-1.70 (m, 2H), 1.59-1.55 (m, 2H), 1.31 (br s, 4H). MS (m/z):341.1 (M + H). 216 404

N-hydroxy-N-(6- (11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)hexyl)formamide ¹H NMR (CD₃OD) δ (ppm): 8.24, 7.89 (2s, rotamers, 1H),7.74 (d, J = 7.6 Hz, 1H), 7.54-7.46 (m, 2H), 7.33 (dt, J = 7.4, 2.0 Hz,1H), 7.28-7.21 (m, 4H), 4.19 (br s, 2H), 3.50 (t, J = 6.8 Hz, 1H),3.44(t, J = 6.8 Hz, 1H), 1.70-1.55 (m, 4H), 1.44-1.29 (m, 4H). MS (m/z):355.2 (M + H). 217 407

2-(dipyridin-2- ylmethylamino)-N- hydroxypyrimidine- 5-carboxamide ¹HNMR (CD₃OD) δ (ppm): 8.65 (bs, 2H), 8.54 (d, J = 4.8 Hz, 2H), 7.79 (dt,J = 2 Hz, 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.31 (dd, J = 2 Hz, 6.8Hz, 2H), 6.43 (s, 1H). MS (m/z): 323.4 (M + H). 218 411

N-hydroxy-7- (11-oxodibenzo [b,f][1,4]thiazepin- 10(11H)-yl) heptanamide¹H NMR (CD₃OD) δ (ppm): 7.63-7.59 (m, 2H), 7.52-7.46 (m, 2H), 7.42-7.34(m, 3H), 7.19 (td, J = 7.4, 1.4 Hz, 1H), 4.70 (dt, J = 13.7, 1.4 Hz,1H), 3.67 (ddd, J = 13.7, 7.4, 5.9 Hz, 1H), 2.04 (t, J = 7.0 Hz, 2H),1.65-1.52 (m, 4H), 1.44-1.22 (m, 4H). MS (m/z): 371.4 (M + H). 219 414

¹H NMR (CD₃OD) δ (ppm): 7.80 (dd, J = 8.0, 2.0 Hz, 1H), 7.61 (ddd, J =8.4, 6.8, 1.2 Hz, 1H), 7.46-7.41 (m, 3H), 7.38-7.30 (m, 3H), 3.62 (t, J= 7.2 Hz, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.61-1.51 (m,4H), 1.44-1.28 (m,4H). MS (m/z): 391.3 (M + H). 220 418

N-hydroxy-3-(4- ((11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)methyl)phenyl) propanamide ¹H NMR (DMSO-d₆) δ (ppm): 10.33 (s, 1H), 8.68(s, 1H), 7.74 (dd, J = 7.6, 1.6 Hz, 1H), 7.60-7.56 (m, 1H), 7.48-7.44(m, 1H), 7.36-7.28 (m, 3H), 7.19-7.10 (m, 6H), 5.31 (s, 2H), 2.73 (t, J= 7.2 Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H). MS (m/z): 389.4 (M + H). 221422

4-(2-(7-chloro-11- oxodibenzo[b,f] [1,4]oxazepin- 10(11H)-yl) ethoxy)-N-hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.04 (s, 1H), 8.90 (s, 1H),7.74-7.71 (m, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.61-7.57 (m, 2H),7.39-7.36 (m, 2H), 7.32 (td, J = 7.4, 1.2 Hz, 1H), 6.91 (d, J = 8.8 Hz,2H), 4.42 (br s, 2H), 4.30 (t, J = 5.2 Hz, 2H). MS (m/z): 447.4 (M +Na). 222 429

¹H NMR (DMSO-d₆) δ (ppm): 9.46 (s, 0.1H), 8.58 (br s, 2H), 7.80 (d, J =7.8 HZ, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.56(t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H),7.27 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 21.7 Hz, 1H), 5.92 (s, 1H). MS(m/z): 361.4 (M − H). 223 433

N-hydroxy-4- (2-(5-oxobenzo [b]pyrido[3,2- f][1,4]oxazepin-6(5H)-yl)ethoxy) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.05 (s, 1H), 8.90(s, 1H), 8.46 (dd, J = 4.8, 2.0 Hz, 1H), 8.23 (dd, J = 7.6, 1.6 Hz, 1H),7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.67 (d, J = 9.2 Hz, 2H), 7.44 (dd, J =7.6, 4.4 Hz, 1H), 7.39-7.25 (m, 3H), 6.90 (d, J = 9.2 Hz, 2H), 4.47 (m,2H), 4.32 (t, J = 5.2 Hz, 2H). MS (m/z): 392.3 (M + H). 224 436

N-hydroxy-4-(3- (11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)prop-1-ynyl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.30 (s, 1H), 9.11 (s, 1H),7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.74-7.72 (m, 3H), 7.64-7.59 (m, 1H),7.47-7.26 (m, 7H), 5.11 (s, 2H) LRMS (ESI):(calc) 384.11 (found) 385.16(MH)+ 225 441

4-(2-(2-fluoro-11- oxodibenzo[b,f] [1,4]oxazepin- 10(11H)-yl) ethoxy)-N-hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.05 (s, 1H), 8.90 (s, 1H),7.70-7.65 (m, 3H), 7.49-7.38 (m, 4H), 7.33-7.23 (m, 2H), 6.89 (d, J =9.0 Hz, 2H), 4.45 (br s, 2H), 4.31 (t, J = 5.2 Hz, 2H) . MS (m/z): 409.3(M + H). 226 444

N-hydroxy-4-(2- (5-oxo-2,3- dihydrobenzo[f] [1,4]oxazepin-4(5H)-yl)ethoxy) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.08 (s, 1H), 8.92(s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H),7.48-7.44 (m, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 7.05-7.01 (m, 3H),4.36 (t, J = 4.7 Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 3.92 (t, J = 5.5 Hz,2H), 3.64 (t, J = 5.1 Hz, 2H). MS (m/z): 343.2 (M + H). 227 449

N-hydroxy-4-(2- (5-oxobenzo[b] pyrido[4,3-f][1,4] oxazepin-6(5H)-yl)ethoxy) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.06 (s, 1H), 8.92 (s,1H), 8.71 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 7.72 (dd, J = 8.4, 1.8 Hz,1H), 7.69-7.66 (m, 3H), 7.44 (dd, J = 8.0, 1.8 Hz, 1H), 7.35-7.26 (m,2H), 6.89 (d, J = 8.8 Hz, 2H), 4.48-4.47 (m, 2H), 4.32 (t, J = 5.4 Hz,2H). MS (m/z): 392.3 (M + H). 228 451

N-hydroxy-3-(4- ((11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)methyl)-1H-1,2,3- triazol-1-yl) propanamide ¹H NMR (CD₃OD) δ (ppm): 7.97(s, 1H), 7.79 (dd, J = 8.4, 1.8 Hz, 1H), 7.68-7.65 (m, 1H), 7.56-7.52(m, 1H), 7.32-7.20 (m, 5H), 5.28 (s, 2H), 4.69 (t, J = 6.8 Hz, 2H), 2.71(t, J = 6.8 Hz, 2H). MS (m/z): 380.3 (M + H). 229 453

N-hydroxy-4-(2- (2-methyl-5- oxo-1,2,3,4- tetrahydrobenzo[b]pyrido[4,3-f] [1,4]oxazepin-6 (5H)-yl)ethoxy) benzamide ¹H NMR(CD₃OD) δ (ppm): 7.65 (d, J = 8.8 Hz, 2H), 7.55 (dd, J = 8.0, 1.2 Hz,1H), 7.27 (td, J = 7.6, 1.6 Hz, 1H), 7.20 (td, J = 8.0, 1.6 Hz, 1H),7.10 (dd, J = 8.0, 1.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 4.38 (t, J =5.2 Hz, 2H), 4.30 (t, J = 5.2 Hz, 2H), 3.34-3.33 (m, 2H), 2.68 (t, J =5.8 Hz, 2H), 2.48 (br s, 5H). MS (m/z): 410.4 (M + H). 230 457

4-(2- (dibenzo[b,f] [1,4]oxazepin- 10(11H)-yl)-2- oxoethoxy)-N-hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.03 (s, 1H), 8.90 (s, 1H),7.70 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.47-7.41 (m, 2H),7.30-7.22 (m, 4H), 7.10-7.06 (m, 1H), 6.75 (d, J = 8.8 Hz, 2H), 5.01-4.66 (m, 4H). MS (m/z): 391.1 (M + H). 231 460

¹H NMR (DMSO-d₆) δ (ppm): 11.06 (s, 1H), 9.06 (s, 1H), 8.59 (s, 2H),7.58-7.47 (m, 6H), 7.40-7.31 (m, 2H), 7.01 (s, 2H). 232 464

N-hydroxy-3-(2- (11-oxodibenzo [b,f][1,4]oxazepin- 10(11 H)-yl)ethoxy)benzamide ¹H NMR (CD₃OD) δ (ppm): 7.77 (dd, J = 8.0, 1.8 Hz, 1H),7.67 (dd, J = 7.8, 1.8 Hz, 1H), 7.58-7.53 (m, 1H), 7.38- 7.22 (m, 8H),7.09-7.04 (m, 1H), 4.59- 4.51 (brs, 2H), 4.42 (t, J = 5.3 Hz, 2H). MS(m/z): 389.2 (M − H). 233 466

N-hydroxy-4-(11- oxodibenzo[b,f] [1,4]oxazepin- 10(11H)-yl) benzamide ¹HNMR (DMSO-d₆) δ (ppm): 11.33 (s, 1H), 9.14 (s, 1H), 7.87 (d, J = 8.8 Hz,2H), 7.81 (dd, J = 8.0, 2.0 Hz, 1H), 7.66- 7.62 (m, 1H), 7.51-7.43 (m,4H), 7.36 (td, J = 7.8, 0.8 Hz, 1H), 7.22 (td, J = 7.4, 1.6 Hz, 1H),7.11 (td, J = 7.8, 1.6 Hz, 1H), 6.76 (dd, J = 8.0, 1.6 Hz, 1H). MS(m/z): 347.2 (M + H). 234 470

(Z)-N-hydroxy- 4-(1-methyl-2- oxo-2,3-dihydro- 1H-benzo[e][1,4]diazepin-5- yl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.33 (s, 1H), 9.12(s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.69-7.65 (m, 1H), 7.62-7.58 (m, 3H),7.31-7.23 (m, 2H), 4.59 (d, J = 10.4 Hz, 1H), 3.76 (d, J = 10.4 Hz, 1H),3.32 (s, 3H). MS (m/z): 310.3 (M + H). 235 475

N-hydroxy-2- (3-phenyl-5,6- dihydro-[1,2,4] triazolo[4,3-a]pyrazin-7(8H)- yl)pyrimidine-5- carboxamide ¹H NMR (DMSO-d₆) δ (ppm):11.19 (s, 1H), 9.09 (s, 1H), 8.79 (s, 2H), 7.78- 7.77 (m, 2H), 7.76-7.75(m, 3H), 5.20-5.15 (m, 2H), 4.35-4.20 (m, 4H). MS (m/z): 338.4 (M + H).236 481

N-hydroxy-2-(3- (trifluoromethyl)- 5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl) pyrimidine-5- carboxamide ¹H NMR (DMSO-d₆) δ(ppm): 11.19 (s, 1H), 9.10 (s, 1H), 8.77 (s, 2H), 5.20 (s, 2H), 4.32 (t,J = 5.1 Hz, 2H), 4.25 (t, J = 4.9 Hz, 2H). MS (m/z): 330.2 (M + H). 237486

4-((6,11- dihydrodibenzo [b,e]oxepin-11- ylamino)methyl)-N-hydroxybenzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.14 (s, 1H), 8.99 (s, 1H),7.70-7.68 (d, J = 7.6 Hz, 2H), 7.38-7.23 (m, 6H), 7.18- 7.14 (m, 2H),6.87 (t, J = 7.0 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 12.4Hz, 1H), 4.91 (d, J = 12.4 Hz, 1H), 4.65 (d, J = 2.8 Hz, 1H), 3.63 (d, J= 5.6 Hz, 2H), 3.07 (brs, 1H). MS (m/z): 361.4 (M + H). 238 490

2-((1R,5S)-1-(3,4- dichlorophenyl)-3- azabicyclo[3.1.0] hexan-3-yl)-N-hydroxypyrimidine- 5-carboxamide ¹H NMR (CD₃OD) δ (ppm): 8.67 (s, 2H),7.46 (m, 2H), 7.23 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 4.31 (d, J = 11.2 Hz,1H), 4.07 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.2 Hz, 2H), 2.14 (quin, J= 4 Hz, 1H), 1.22 (m, 1H), 0.90 (t, J = 4.8 Hz, 1H). MS (m/z): 363.4 (M− H). 239 495

(Z)-4-(7-bromo- 2-oxo-2,3-dihydro- 1H-thieno[2,3- e][1,4]diazepin-5-yl)-N- hydroxybenzamide ¹H NMR (CD₃OD) δ (ppm): 7.84 (d, J = 8.4 Hz,2H),7.66 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 4.36 (s, 2H). MS (m/z):378.2 (M − H). 240 497

N-hydroxy-4- ((2-phenyl-1H- indol-1-yl)methyl) benzamide ¹H NMR (CD₃OD)δ (ppm): 7.66-7.62 (m, 3H), 7.50-7.38 (m, 5H), 7.28-7.23 (m, 1H),7.17-7.08 (m, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 0.6 Hz, 1H),5.51 (s, 2H). MS (m/z): 343.5 (M + H). 241 502

(S)-2-(2-(1H- benzo[d]imidazol- 2-yl)pyrrolidin-1- yl)-N-hydroxypyrimidine- 5-carboxamide ¹H NMR (CD₃OD) δ (ppm): 8.72 (bs, 1H),8.50 (bs, 1H), 7.46 (s, 2H), 7.17 (m, 2H), 5.48 (d, J = 8.0 Hz, 1H),4.04 (m, 1H), 3.79 (m, 1H), 2.53 (m, 1H), 2.28 (m, 1H), 2.14 (m, 2H). MS(m/z): 325.3 (M + H). 242 504

(Z)-N-(4-((5H- dibenzo[b,f] azepin-5-yl) methyl)benzyl)-N-hydroxyformamide ¹H NMR (CD₃OD) δ (ppm): 8.29 (s, 0.5H), 8.10 (s, 0.5H),7.46 (t, J = 8.6 Hz, 2H), 7.18-7.12 (m, 4H), 7.09 (d, J = 7.6 Hz, 2H),7.04 (dd, J = 7.7 and 1.4 Hz, 2H), 6.93 (td, J = 7.4 and 0.8 Hz, 2H),6.90 (s, 2H), 4.95 (d, J = 3.0 Hz, 2H), 4.58 (s, 1H), 4.53 (s, 1H). MS(m/z): 357.3 (M + H). 243 505

(Z)-4-(5H-dibenzo [b,f]azepin-5-yl)-N- hydroxybutanamide ¹H NMR (CD₃OD)δ (ppm): 7.27-7.22 (2H, m), 7.05 (4H, dd, J = 7.7, 1.8 Hz), 6.99-6.95(2H, m), 6.73 (2H, s), 3.74 (2H, t, J = 6.7 Hz), 2.16 (2H, 1, J = 7.4Hz), 1.83-1.79 (2H, m). MS (m/z): 295.1 (M + H). 244 506

(Z)-6-(5H-dibenzo [b,f]azepin-5-yl)-N- hydroxyhexanamide ¹H NMR (CD₃OD)δ (ppm): 7.25-7.19 (2H, m), 7.03-6.98 (4H, m), 6.95-6.91 (2H, m), 6.67(2H, s), 3.65 (2H, t, J = 6.7 Hz), 1.97 (2H, t, J = 7.6 Hz), 1.55- 1.45(4H, m), 1.4-1.3(2H, m). MS(m/z): 323.1 (M + H). 245 507

(Z)-N-hydroxy- 8-(2-oxo-5-phenyl- 2,3-dihydro-1H- benzo[e][1,4]diazepin-1-yl) octanamide ¹H NMR (CD₃OD) δ (ppm): 7.69-7.62 (m, 2H),7.56-7.50 (m, 3H), 7.47-7.43 (m, 2H), 7.33-7.27 (m, 2H), 4.59 (d, J =10.6 Hz, 1H), 4.48-4.41 (m, 1H), 3.83 (d, J = 10.6 Hz, 1H), 3.78-3.71(m, 1H), 1.91 (t, J = 6.3 Hz, 2H), 1.52-1.49 (m, 1H), 1.39 (quintet, J =7.6 Hz, 3H), 1.18 -1.03 (m, 6H). MS (m/z): 394.2 (M + H). 246 508

¹H NMR (CD₃OD) δ (ppm): 7.37-7.26 (1H, m), 7.26-7.40 (7H, m), 6.11 (1H,s), 3.26-2.90 (4H, br m). MS (m/z): 266.0 (M + H). 247 509

¹H NMR (CD₃OD) δ (ppm): 7.49 (d, J = 7.7 Hz, 1H), 7.30-7.12 (m, 7H),4.12 (t, J = 6.5 Hz, 2H), 3.18-3.00 (m, 4H), 2.05 (t, J = 7.4 Hz, 2H),1.75-1.55 (m, 4H), 1.42-1.22 (m, 4H). MS (m/z): 367.1 (M + H). 248 510

¹H NMR (CD₃OD) δ (ppm): 7.27 (d, J = 6.9 Hz, 1H), 7.35-7.12 (m, 7H),4.14 (t, J = 6.4 Hz, 2H), 3.18-3.00 (m, 4H), 2.07 (t, J = 7.5 Hz, 2H),1.75-1.55 (m, 4H), 1.42-1.32 (m, 2H). MS (m/z): 353.1 (M + H). 249 511

¹H NMR (CD₃OD) δ (ppm): 7.55 (1H, dd, J = 7.7, 1.2 Hz), 7.35-7.2 (6H,m), 7.19-7.10 (1H, m), 4.18 (2H, t, J = 5.3 Hz), 3.16-3.05 (4H, m),2.26-2.16 (2H, m), 2.10-1.98 (2H, m). MS (m/z): 325.0 (M + H). 250 512

¹H NMR (CD₃OD) δ (ppm): 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.46 (d, J = 7.5Hz, 1H), 7.30-7.22 (m, 3H), 7.21-7.15 (m, 3H), 4.53 (s, 2H), 3.18-3.02(m, 4H). MS (m/z): 297.0 (M + H). 251 513

¹H NMR (DMSO-d₆) (ppm): 7.69 (2H, d, J = 8.2 Hz), 7.40 (1H, dd, J = 7.7,1.3 Hz), 7.33-7.12 (9H, m), 5.16 (2H, s), 3.06- 2.95 (4H, m). MS (m/z):373.1 (M + H). 252 514

6-(11-cyclopropyl- 5-oxo-5H-benzo [b]pyrido[2,3- e][1,4]diazepin-6(11H)-yl)-N- hydroxyhexanamide ¹H NMR (CD₃OD) δ (ppm): 8.36 (dd, J =4.7, 1.8 Hz, 1H), 8.00 (dd, J = 7.6, 2.0 Hz, 1H), 7.52 (dd, J = 8.0, 1.3Hz, 1H), 7.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.30-7.17 (m, 2H), 7.14-7.10(m, 1H), 4.62-4.52 (m, 1H), 3.70-3.55 (m, 2H), 2.05-2.00 (m, 2H),1.62-1.38 (m, 4H), 1.33-1.20 (m, 2H), 1.08-0.97 (m, 2H), 0.60-0.50 (m,1H), 0.40-0.30 (m, 1H). MS (m/z): 381.2 (M + H). 253 515

7-(11-cyclopropyl- 5-oxo-5H-benzo [b]pyrido[2,3-e] [1,4]diazepin-6(11H)-yl)-N- hydroxyheptanamide ¹H NMR (CD₃OD) δ (ppm): 8.37 (dd, J =4.6, 2.0 Hz, 1H), 8.00 (dd, J = 7.9, 2.1 Hz, 1H), 7.52 (dd, J = 8.2, 1.4Hz, 1H), 7.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.30-7.17 (m, 2H), 7.14-7.10(m, 1H), 4.65-4.52 (m, 1H), 3.70-3.55 (m, 2H), 2.02 (t, J = 7.4 Hz, 2H),1.60-1.45 (m, 3H), 1.44-1.33 (m, 1H), 1.32-1.16 (m, 4H), 1.08-0.87 (m,2H), 0.60-0.50 (m, 1H), 0.42-0.35 (m, 1H). MS (m/z): 395.1 (M + H). 254516

4-((11-cyclopropyl- 5-oxo-benzo[b] pyrido[2,3-e][1,4] diazepin-6(11H)-yl)methyl)-N- hydroxybenzamide ¹H NMR (CD₃OD) δ (ppm): 8.42-8.38 (m,1H), 8.10-8.04 (m, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.47-7.40 (m, 2H),7.30 (d, J = 8.3 Hz, 2H), 7.22-7.10 (m, 3H), 5.82 (d, J = 15.7 Hz, 1H),5.00-4.80 (m, 1H), 3.61-3.50 (m, 1H), 1.03-0.97 (m, 1H), 0.88-0.80 (m,1H), 0.60-0.54 (m, 1H), 0.23-0.17 (m, 1H). MS (m/z): 401.0 (M + H). 256518

8-(11-cyclopropyl- 5-oxo-5H-benzo [b]pyrido[2,3-e] [1,4]diazepin-6(11H)-yl)-N- hydroxyoctanamide ¹H NMR (CD₃OD) δ (ppm): 8.36 (dd, J =5.9, 2.0 Hz, 1H), 8.00 (dd, J = 7.6, 2.0 Hz, 1H), 7.52 (dd, J = 8.1, 1.5Hz, 1H), 7.36 (dd, J = 7.9, 1.6 Hz, 1H), 7.30-7.17 (m, 2H), 7.14-7.10(m, 1H), 4.65-4.57 (m, 1H), 3.66-3.57 (m, 2H), 2.05-2.01 (m, 2H),1.62-1.18 (m, 11H), 1.08-0.90 (m, 2H), 0.56-0.50 (m, 1H), 0.42-0.38 (m,1H). MS (m/z): 409.1 (M + H). 257 519

(E)-N-hydroxy-3- (4-(((Z)-2-oxo-5- phenyl-2,3- dihydro-1H- benzo[e][1,4]diazepin-1-yl) methyl)phenyl) acrylamide ¹H NMR (DMSO-d₆) δ (ppm): 7.65(d, J = 1.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.51- 7.46 (m, 1H), 7.39 (t, J =7.8 Hz, 2H), 7.34-7.28 (m, 5H), 7.21-7.17 (m, 1H), 7.17-7.10 (m, 1H),6.99 (d, J = 8.0 Hz, 2H), 6.32 (d, J = 15.8 Hz, 1H), 5.45 (d, J = 16.0Hz, 1H), 4.93 (d, J=16.0 Hz, 1H), 4.62 (d, J = 10.4 Hz, 1H), 3.83(d, J =10.4 Hz, 1H). MS (m/z): 412.2 (M + H). 258 520

(E)-3-(4-(((Z)- 5H-dibenzo[b,f] azepin-5-yl) methyl)phenyl)-N-hydroxyacrylamide ¹H NMR (CD₃OD) δ (ppm): 7.48 (1H, d, J = 1.5 Hz), 7.45(2H, d, J = 10.0 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.19-7.13 (2H, m), 7.08(2H, d, J = 7.6 Hz), 7.05 (2H, dd, J = 7.6, 1.6 Hz), 6.92 (2H, td, J =7.4, 0.9 Hz), 6.79 (2H, s), 6.34 (1H, d, J = 15.9 Hz), 4.96 (2H, s). MS(m/z): 369.2 (M+H). 259 521

(E)-3-(4-((11- cyclopropyl-5- oxo-5H-benzo [b]pyrido[2,3-e][1,4]diazepin- 6(11H)-yl)methyl) phenyl)-N- hydroxyacrylamide ¹H NMR(CD₃OD) δ (ppm): 8.41-8.36 (1H, m), 8.07 (1H, d, J = 7.6, 1.8 Hz), 7.49(1H, d, J = 15.8 Hz), 7.46-7.40 (4H, m), 7.26-7.10 (5H, m), 6.40 (1H, d,J = 15.8 Hz), 5.80 (1H, d, J = 15.4 Hz), 4.84 (1H, d, J = 15.7 Hz),3.60-3.50 (1H, m), 1.02-0.92 (1H, m), 0.84-0.74 (1H, m), 0.58-0.48 (1H,m), 0.16-0.06 (1H, m). MS (m/z): 427.2 (M + H). 260 522

6-(10,11-dihydro- 5H-dibenzo[b,f] azepin-5-yl)-N- hydroxyhexanamide ¹HNMR (CDCl₃) δ (ppm): 7.11-7.02 (m, 6H), 6.87 (t, J = 7.4 Hz, 2H), 3.60(t, J = 6.6 Hz, 2H), 1.87-1.77 (m, 2H), 3.10 (s, 4H), 1.51-1.33 (m,4H),1.26- 1.14 (m, 2H). MS (m/z): 325.2 (M + H). 261 523

¹H NMR(CD₃OD) δ (ppm): 7.23-7.19 (2H, m), 7.11-7.06 (6H, m), 4.65 (1H,t, J = 7.8 Hz), 3.4-3.31 (2H, m), 3.05- 2.98 (2H, m), 2.80 (2H, d, J =7.8 Hz). 262 524

¹H NMR (CD₃OD) δ (ppm): 7.55-7.53 (m, 2H), 7.45-7.36 (m, 6H), 6.93 (s,2H), 4.16-4.02 (m, 2H), 2.06 (t, J = 7.2 Hz, 2H), 1.68-1.57 (m, 4H),1.39-1.31 (m, 2H). MS (m/z): 351.0 (M + H). 263 525

¹H NMR (CD₃OD) δ (ppm): 7.53-7.51 (m, 1H), 7.32-7.14 (m, 7H), 4.16 (t, J= 5.6 Hz, 2H), 3.12-3.04 (m, 4H), 2.12-2.09 (m, 2H), 1.68 (br s, 4H). MS(m/z): 339.2 (M + H). 264 526

N-hydroxy-7-(11- oxodibenzo[b,f] [1,4]oxazepin- 10(11H)-yl) heptanamide¹H NMR (CD₃OD) δ (ppm): 7.75-7.23 (m, 1H), 7.54-7.50 (m, 1H), 7.46 (dd,J = 7.8, 1.6 Hz, 1H), 7.32 (dd, J = 7.4, 2.2 Hz, 1H), 7.28-7.20 (m, 4H),4.18 (br s, 2H), 2.04 (t, J = 7.4 Hz, 2H), 1.70-1.53 (m, 4H), 1.41-1.28(m, 4H). MS (m/z): 355.2 (M + H). 265 527

2-(benzhydryl- amino)-N- hydroxypyrimidine- 5-carboxamide ¹H NMR(DMSO-d₆) δ (ppm): 11.01 (s, 1H), 8.99 (s, 1H), 8.77 (d, J = 9.4 Hz,1H), 8.61 (s, 2H), 7.38 (d, J = 7.4 Hz, 4H), 7.31 (t, J = 7.5 Hz, 4H),7.22 (t, J = 7.3 Hz, 2H), 6.43 (d, J = 9.2 Hz, 1H). MS (m/z): 319.2 (M −H). 266 528

2-(diphenyl- methylene- aminooxy)-N- hydroxypyrimidine- 5-carboxamide ¹HNMR (DMSO-d₆) δ (ppm): 11.3 (s, 1H), 8.64 (s, 2H), 7.26-7.4 (m, 10H),6.42 (s, 1H). 267 529

N-hydroxy-6-(11- oxodibenzo[b,f] [1,4]oxazepin- 10(11H)-yl) hexanamide¹H NMR (CD₃OD) δ (ppm): 7.73 (dd, J = 8.2, 2.0 Hz, 1H), 7.54-7.45 (m,2H), 7.31 (dd, J = 7.4, 2.2 Hz, 1H), 7.27-7.19 (m, 4H), 4.17 (brs, 2H),2.05 (t, J = 7.0 Hz, 2H), 1.71-1.57 (m, 4H), 1.41-1.34 (m, 2H). MS(m/z): 341.1 (M + H). 268 530

N-hydroxy-8- (11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl) octanamide¹H NMR (CD₃OD) δ (ppm): 7.73 (dd, J = 8.0, 1.8 Hz, 1H), 7.53-7.45 (m,2H), 7.33-7.20 (m, 5H), 4.18 (br s, 2H), 2.05 (t, J = 7.4 Hz, 2H),1.68-1.54 (m, 4H), 1.33-1.29 (m,6H). MS (m/z): 369.2 (M + H). 269 531

2-(9H-fluoren- 9-ylamino)-N- hydroxypyrimidine- 5-carboxamide ¹H NMR(DMSO-d₆) δ (ppm): 8.68 (br s, 2H), 8.23 (d, J = 8.8 Hz, 1H), 7.85 (d, J= 7.7 Hz, 2H), 7.47 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.28(t, J = 7.4 Hz, 2H), 6.33 (m, 1H). MS (m/z): 319.2 (M + H). 270 532

¹H NMR (DMSO-d₆) δ (ppm): 11.05 (br s, 1H), 8.99 (br s, 1H), 8.62 (s,2H), 7.22-7.04 (m, 8H), 4.05 (s, 1H), 4.01-3.90 (m, 2H), 3.72 (s, 4H),2.82-2.70 (m, 2H), 2.29- 2.20 (m, 4H). MS (m/z): 414.2 (M + H). LRMS:415.2 (calc), 414.2 (MH)− 271 533

¹H NMR (CD₃OD) δ (ppm): 8.64 (m, 1H), 8.49 (m, 1H), 7.06-7.17 (m, 8H),4.40 (t, J = 8 Hz, 1H), 4.00 (d, J = 8 Hz, 2H), 3.44 (m, 2H), 2.96 (m,2H). MS (m/z): 359.3 (M − H). 272 534

8-(dibenzo[b,f] [1,4]oxazepin- 10(11H)-yl)-N- hydroxy-8- oxooctanamide¹H NMR (CD₃OD) δ (ppm): 7.44-7.38 (m, 2H), 7.36-7.31 (m, 1H), 7.30-7.14(m, 4H), 7.04 (t, J = 7.4 Hz, 1H), 6.00-5.20 (m, 1H), 4.50-4.00 (m, 1H),2.28-2.18 (m, 2H), 1.99 (t, J = 7.5 Hz, 2H), 1.56- 1.40 (m, 4H),1.22-1.08 (m, 4H). MS (m/z): 369.4 (M + H). 273 535

¹H NMR (DMSO-d₆) δ (ppm): 8.71 (s, 2H), 7.37 (s, 1H), 7.31 (d, J = 7.0Hz, 2H), 7.20- 7.13 (m, 6H), 3.30-3.17 (m, 2H), 3.02-2.94 (m, 2H), 2.90(s, 3H). MS (m/z): 359.3 (MH)−. 274 536

N-hydroxy-4- ((11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)methyl)benzamide ¹H NMR (CD₃OD) δ (ppm): 7.81-7.79 (m, 1H), 7.69 (dt, J= 8.4, 2.0 Hz, 2H), 7.58- 7.53 (m, 1H), 7.42-7.36 (m, 3H), 7.31-7.27 (m,3H), 7.18-7.12 (m, 2H), 5.43 (s, 2H). MS (m/z): 361.3 (M + H). 275 537

¹H NMR (DMSO-d₆) δ (ppm): 11.01 (s, 1H), 8.99 (s, 1H), 8.68-8.51 (m,2H), 7.72 (d, J = 7.8 Hz, 2H), 7.42-7.38 (m, 4H), 7.29-7.24 (m, 4H),5.95 (br s, 1H). MS (m/z): 343.5 (M − H). 276 538

2-(bis(4- fluorophenyl) methylamino)-N- hydroxypyrimidine- 5-carboxamide¹H NMR (CD₃OD) δ (ppm): 8.62 (s, 2H), 7.32 (m, 4H), 7.04 (t, J = 8.4 Hz,4H), 6.40 (s, 1H). MS (m/z): 355.3 (M − H). 277 539

N-hydroxy-4-((6- oxophenanthridin- 5(6H)-yl)methyl) benzamide ¹H NMR(DMSO-d₆) δ (ppm) 11.05 (br s, 1H), 9.00 (br s, 1H), 8.58 (d, J = 8.2Hz, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.45-8.40 (m, 1H), 7.94-7.86 (m, 1H),7.73-7.62 (m, 3H), 7.49-7.43 (m, 1H), 7.40-7.34 (m, 1H), 7.34- 7.28 (m,1H), 7.28-7.23 (m, 2H), 5.66 (s, 2H). MS (m/z): 343.3 (MH)−. 278 540

N-hydroxy-4-(2- (11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)ethoxy)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.06 (s, 1H), 8.91 (s, 1H),7.73-7.66 (m, 4H), 7.59-7.54 (m, 1H), 7.39-7.21 (m, 5H), 6.91 (d, J =9.0 Hz, 2H), 4.45 (br s, 2H), 4.33 (t, J = 5.5 Hz, 2H). MS (m/z): 413.4(M + Na). 279 541

N-hydroxy-7- (phenanthridin- 6-yloxy) heptanamide ¹H NMR (DMSO-d₆) δ(ppm): 10.33 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 8.66 (br s, 1H), 8.62(d, J = 8.3 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.95-7.88 (m, 1H),7.80-7.70 (m, 2H), 7.68-7.60 (m, 1H), 7.54-7.48 (m, 1H), 4.55 (t, J =16.4 Hz, 2H), 1.95 (t, J = 7.2 Hz, 2H), 1.91-1.81 (m, 2H), 1.58-1.45(m,4H), 1.42-1.30 (m, 2H). MS (m/z): 339.4 (M + H). 280 542

N-hydroxy-7-(6- oxophenanthridin- 5(6H)-yl) heptanamide ¹H NMR (CDCl₃) δ(ppm): 9.47 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 8.28 (t, J = 8.6 Hz, 2H),7.80-7.72 (m, 1H), 7.62-7.51 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (t,J = 7.5 Hz, 1H), 4.38 (t, J = 7.3 Hz, 2H), 2.22 (t, J = 7.0 Hz, 2H),1.86-1.62 (m, 4H), 1.52-1.42 (m,4H). MS (m/z): 337.4 (MH)−. 281 543

N-hydroxy-2-(4- ((11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)methyl)phenyl) acetamide ¹H NMR (DMSO-d₆) δ (ppm): 10.62 (s, 1H), 8.79(s, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (ddd, J = 8.0, 7.2, 1.6Hz, 1H), 7.49- 7.46 (m, 1H), 7.38-7.30 (m, 3H), 7.21-7.14 (m, 6H), 5.33(s, 2H), 3.22 (s, 2H). MS (m/z): 397.4 (M + Na). 282 544

6-(5-cyclopropyl- 11-oxo-5H- dibenzo[b,e][1,4] diazepin-10(11H)-yl)-N-hydroxyhexanamide 7.70 (d, J = 7.6 Hz, 1H), 7.42-7.35 (m, 2H),7.28 (d, J = 8.4 Hz, 1H), 7.25-7.00 (m, 4H), 4.65-4.55 (m, 1H),3.63-3.53 (m, 1H), 3.25- 3.05 (m, 1H), 2.20-2.05 (m, 2H) 1.76-1.40(m,4H), 1.39-1.10 (m, 2H), 1.00-0.08 (m, 2H) 0.07-0.05 (m, 1H),0.05-0.04 (m, 1H). MS (m/z): 378.4 (MH)− 283 545

7-(5-cyclopropyl- 11-oxo-5H- dibenzo[b,e][1,4] diazepin-10(11H)- yl)-N-hydroxyheptanamide 7.70 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H),7.25-7.02 (m, 5H), 4.78-4.60 (m, 1H), 3.46-3.60 (m, 1H), 3.27-3.18 (m,1H), 2.18- 1.95 (m, 2H), 1.80-1.01 (m, 8H), 1.00-0.82 (m, 2H), 0.65-0.59(m, 1H), 0.58-0.43 (m, 1H). MS (m/z): 392.5 (MH)− 284 546

(E)-N-hydroxy-3- (4-((11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)methyl)phenyl) acrylamide ¹H NMR (DMSO-d₆) δ (ppm): 10.75 (s, 1H), 9.04(s, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.63-7.58 (m, 1H), 7.51-7.30(m, 9H), 7.21-7.15 (m, 2H), 6.40 (d, J = 15.6 Hz, 1H), 5.38 (s, 2H). MS(m/z): 387.3 (M + H). 285 547

N-hydroxy-4- ((6-oxo-11,12- dihydrodibenzo [b,f]azocin-5(6H)- yl)methyl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.21 (s, 1H), 9.03 (s, 1H), 7.69(d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.16-6.95 (m, 8H), 5.26(d, J = 14.4 Hz, 1H), 4.77 (d, J = 14.4 Hz, 1H), 3.19-3.11 (m, 1H),2.90-2.83 (m, 1H), 2.71-2.55 (m, 2H). MS (m/z): 373.2 (M + H). 287 549

¹H NMR (DMSO-d₆) δ (ppm): 7.56 (d, J = 7.4 Hz, 2H), 7.42-7.36 (m, 4H),7.28-7.26 (m, 2H), 7.17 (s, 2H), 5.63 (s, 1H), 2.26 (br s, 2H), 1.90 (t,J = 7.4 Hz, 2H), 1.52-1.36 (m, 4H), 1.30-1.10 (m, 4H). MS (m/z): 377.5(M − H). 288 550

(Z)-8-(5H-dibenzo [b,f]azepin-5-yl)- N-hydroxy-8- oxooctanamide ¹H NMR(DMSO-d₆) δ (ppm): 10.28 (s, 1H), 8.64 (s, 1H), 7.59-7.31 (m, 8H), 7.02(s, 2H), 2.19-2.10 (m, 1H), 1.84 (t, J = 7.4 Hz, 2H), 1.81-1.71 (m, 1H),1.40-1.20 (m, 4H), 1.15- 0.99 (m, 4H). MS (m/z): 363.4 (M − H). 289 551

(Z)-7-(5H-dibenzo [b,f]azepin-5-yl)- N-hydroxy-7- oxoheptanamide ¹H NMR(DMSO-d₆) δ (ppm): 10.28 (s, 1H), 8.63 (s, 1H), 7.60-7.30 (m, 8H), 7.03(s, 2H), 2.21-2.09 (m, 1H), 1.82 (t, J = 7.4 Hz, 2H), 1.79-1.69 (m, 1H),1.41-1.24 (m, 4H), 1.09-0.85 (m, 2H). MS (m/z): 351.4 (M + H). 290 552

¹H NMR (DMSO-d₆) δ (ppm): 10.33 (s, 1H), 8.69 (s, 1H), 7.56 (d, J = 7.6Hz, 2H), 7.43-7.35 (m, 4H), 7.29-7.23 (m, 2H), 7.17 (s, 2H), 5.63 (s,1H), 2.34-2.18 (m, 2H), 1.90 (t, J = 7.5 Hz, 2H), 1.54-1.40 (m, 4H),1.25-1.11 (m, 2H). MS (m/z): 363.4 (M − H). 291 553

(E)-N-hydroxy-4- (3-(11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)prop-1-enyl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.20 (s, 1H), 9.00 (s, 1H),7.76 (dd, J = 7.6, 1.6Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.62-7.55 (m,2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41-7.20 (m, 5H), 6.65 (d, J = 16.0 Hz,1H), 6.53 (dt, J = 16.0, 4.4 Hz, 1H), 4.86 (d, J = 4.4 Hz, 2H). MS (m/z)387.2 (M + H). 292 554

N-hydroxy-4-(3- (11-oxodibenzo [b,f][1,4]oxazepin- 10(11H)-yl)propyl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.13 (s, 1H), 8.97 (s, 1H),7.71 (dd, J = 8.0. 2.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.59- 7.54 (m,1H), 7.43-7.40 (m, 1H), 7.35 (dd, J = 8.0, 0.8 Hz, 1H), 7.31-7.22 (m,3H), 7.17 (d, J = 8.4 Hz, 2H), 4.12 (br s, 2H), 2.62 (t, J = 7.6 Hz,2H), 1.92-1.86 (m, 2H). MS (m/z): 389.3 (M + H). 293 555

N-hydroxy-4-(2- (4-oxo-3,4- dihydrobenzo[b] [1,4]oxazepin-5(2H)-yl)ethoxy) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 11.05 (s, 1H), 8.90(s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.58- 7.55 (m, 1H), 7.28-7.21 (m,2H), 7.14-7.12 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 4.45 (t, J = 6.8 Hz,2H), 4.18-4.15 (m, 2H), 4.10- 4.07 (m, 2H), 2.53 (t, J = 6.8 Hz, 2H). MS(m/z): 343.3 (M + H). 294 556

¹H NMR (DMSO-d₆) δ (ppm): 10.87 (s, 1H), 8.82 (s, 1H), 8.34 (d, J = 2.0Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 7.3, 2.3 Hz, 1H),7.45-7.40 (m, 2H), 7.18-7.06 (m, 6H), 6.81-6.75 (m, 2H), 3.23 (s, 4H).MS (m/z): 346.2 (M + H). 295 557

2-fluoro-N- hydroxy-4-(2-(11- oxodibenzo[b,f] [1,4]oxazepin- 10(11H)-yl)ethoxy)benzamide ¹H NMR (CD₃OD) δ (ppm): 7.72 (d, J = 8.0 Hz, 1H),7.62-7.56 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.29 - 7.17 (m, 5H), 6.74(d, J = 8.8 Hz, 1H), 6.68 (d, J = 12.7 Hz, 1H), 4.49 (br s, 2H),4.38-4.34 (m, 2H). MS (m/z): 409.2 (M + H). 296 558

3-fluoro-N- hydroxy-4-(2- (11-oxodibenzo [b,f][1,4] oxazepin-10(11H)-yl)ethoxy) benzamide ¹H NMR (CD₃OD) δ (ppm): 7.75-7.71 (m, 2H),7.54-7.46 (m, 3H), 7.31-7.15 (m, 6H), 4.51 (s, 4H). MS (m/z): 409.2 (M +H). 297 559

(Z)-3-((5H- dibenzo[b,f] azepin-5- yl)methyl)-N- hydroxybenzamide ¹H NMR(CD₃OD) δ (ppm): 7.90-7.86 (m, 1H), 7.70-7.65 (m, 1H), 7.51-7.46 (m,1H), 7.28 (t, J = 7.6 Hz, 1H), 7.23- 7.06 (m, 6H), 6.98-6.93 (m, 2H),6.83 (s, 2H), 5.03 (s, 2H). MS (m/z): 343.4 (M + H). 298 560

benzyl 4-(5- (hydroxycarb- amoyl)pyrimidin- 2-yl)-1,4- diazepane-1-carboxylate ¹H NMR (DMSO-d₆) δ (ppm): 11.05 (s, 1H), 9.05 (s, 1H),8.65 (s, 2H), 7.33-7.17 (m, 5H), 5.74 (s, 1H), 5.01 (s, 1H), 3.93- 3.83(m, 2H), 3.82-3.70 (m, 2H), 3.62 (t, J = 5.9 Hz, 1H), 3.56 (t, J = 5.6Hz, 1H), 3.45-3.30 (m, 2H), 1.8-1.68 (m, 2H). MS (m/z): 372.4 (M + H).299 561

4-((10,11-dihydro- 5H-dibenzo[b,f] azepin-5- yl)methyl)-N-hydroxybenzamide ¹H NMR (CD₃OD) δ (ppm): 7.62 (d, J = 8.2 Hz, 2H), 7.53(d, J = 8.4 Hz, 2H), 7.19-7.02 (m, 6H), 6.92-6.84 (m, 2H), 5.03 (s, 2H),3.24 (s, 4H). MS (m/z): 345.4 (M + H). 300 562

2-(4-(3-chloro-5- (trifluoromethyl) pyridin-2-yl)- 1,4-diazepan-1-yl)-N- hydroxypyrimidine- 5-carboxamide ¹H NMR (CD₃OD) δ (ppm): 8.64 (s,1H), 8.59 (s, 1H), 8.25 (s, 1H), 7.81 (s, 1H), 4.10 (t, J = 5.6 Hz, 2H),4.01 (t, J = 5.6 Hz, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 5.6 Hz,2H), 2.08 (m, 2H). MS (m/z) 415.4 (M − H). 301 563

3-((10H- phenothiazin-10- yl)methyl)-N- hydroxybenzamide ¹H NMR(DMSO-d₆) δ (ppm): 11.25 (br s, 1H), 9.08 (br s, 1H), 7.84-7.80 (m, 1H),7.64-7.59 (m, 1H), 7.50-7.39 (m,2H), 7.22-7.07 (m, 4H), 6.98-6.92 (m,2H), 6.86-6.80 (m, 2H) 5.21 (s, 2H). MS (m/z): 349.4 (M + H). 302 564

4-(dibenzo[b,f] [1,4]oxazepin- 10(11H)- ylmethyl)-N- hydroxybenzamide ¹HNMR (CD₃OD) δ (ppm): 7.79-7.73 (m, 2H), 7.52-7.46 (m, 2H), 7.34-7.28 (m,1H), 7.23-7.18 (m, 1H), 7.16-7.07 (m, 3H), 6.96-6.77 (m, 3H), 4.46 (s,2H), 4.42 (s, 2H). MS (m/z): 347.4 (M + H). 303 565

4-((benz- hydrylamino) methyl)-N- hydroxybenzamide ¹H NMR (CD₃OD) δ(ppm): 7.77-7.72 (m, 2H), 7.46-7.40 (m, 6H), 7.35-7.30 (m, 4H),7.26-7.21 (m, 2H), 4.82 (s, 1H), 3.78 (s, 2H). MS (m/z): 333.4 (M + H).304 566

¹H NMR (CD₃OD) δ (ppm): 7.73-7.70 (m, 1H), 7.65-7.61 (m, 1H), 7.52-7.48(m, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.29- 7.24 (m, 2H), 7.22-7.11 (m,6H), 4.89 (s, 1H), 3.82-3.67 (m, 4H), 3.04-2.90 (m, 2H). MS (m/z): 359.5(M + H). 305 567

4-((6,7,8,9,10,11- hexahydro- 5H-cycloocta[b] indol-5-yl) methyl)-N-hydroxybenzamide ¹H NMR (CD₃OD) δ (ppm): 7.44-7.40 (m, 1H), 7.34-7.25(m, 4H), 7.21-7.18 (m, 1H), 6.67 (d, J = 8.2 Hz, 2H), 3.19 (dd, J =31.7, 13.9 Hz, 2H), 2.98-2.90 (m, 1H), 2.74 (dt, J = 12.9, 4.7 Hz, 1H),2.63-2.54 (m, 1H), 2.32 (dt, J = 14.7, 4.1 Hz, 1H), 2.22 - 2.16 (m, 1H),1.86- 1.67 (m, 2H), 1.55-1.29 (m, 3H), 1.04- 0.95 (m, 1H), 0.80-0.70 (m,1H). MS (m/z): 349.5 (M + H). 306 568

N-hydroxy-2- methyl-2,3,4,5- tetrahydro-1H- pyrido[4,3-b] indole-8-carboxamide ¹H NMR (DMSO-d₆) δ (ppm): 11.08 (s, 1H), 10.98 (br s, 1H),8.18 (s, 1H), 7.80 (s, 1H), 7.45 (dd, J = 8.5, 1.6 Hz, 1H), 7.27 (d, J =8.4 Hz, 1H), 3.61 (s, 2H), 2.84-2.76 (m, 4H), 2.47 (s, 3H). MS (m/z):246.3 (M + H). 307 569

N-hydroxy- 9H-pyrido[3,4- b]indole-3- carboxamide ¹H NMR (DMSO-d₆) δ(ppm): 11.97 (s, 1H), 11.28 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.83(s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 7.72-7.60 (m, 2H), 7.36-7.31 (m, 1H),MS (m/z): 228.2 (M + H). 308 570

2-((1S,5R)-1-(3,4- dichlorophenyl)-3- azabicyclo[3.1.0] hexan-3-yl)N-hydroxypyrimidine- 5-carboxamide ¹H NMR (CD₃OD) δ (ppm): 8.67 (s, 2H),7.46 (m, 2H), 7.23 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 4.31 (d, J = 11.2 Hz,1H), 4.07 (d, J = 11.2 Hz, 1H), 3.76 (d, J = 11.2 Hz, 2H), 2.14 (quin, J= 4 Hz, 1H), 1.22 (m, 1H), 0.90 (t, J = 4.8 Hz, 1H). MS (m/z): 363.5 (M− H). 309 571

N-hydroxy-2- ((1R,5S)-1- phenyl-3- azabicyclo[3.1.0] hexan-3-yl)pyrimidine-5- carboxamide ¹H NMR (DMSO-d₆) δ (ppm): 8.67 (s, 2H),7.21-7.33 (m, 5H), 4.31 (d, J = 11.2 Hz, 1H), 4.05 (d, J = 11.2 Hz, 1H),3.76 (m, 2H), 2.10 (quin, J = 4 Hz, 1H), 1.18 (m, 1H), 0.84 (t, J = 4.4Hz, 1H). MS (m/z): 295.4 (M − H). 310 572

3-((10H- phenoxazin- yl)methyl)-N- hydroxybenzamide ¹H NMR (DMSO-d₆) δ(ppm): 11.28 (s, 1H), 9.06 (s, 1H), 7.76 (s, 1H), 7.67-7.61 (m, 1H),7.47-7.42 (m, 2H), 6.81-6.57 (m, 6H), 6.51 (dd, J = 7.8, 1.4 Hz, 2H),4.95 (s, 2H). MS (m/z): 331.5 (M − H). 311 573

4- ((diphenylamino) methyl)-N- hydroxybenzamide ¹H NMR (DMSO-d₆) δ(ppm): 11.13 (s, 1H), 9.00 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.26-7.21 (m, 4H), 7.04 (dd, J = 8.6, 1.0 Hz, 4H),6.93-6.89 (m, 2H), 5.05 (s, 2H). MS (m/z): 319.4 (M + H). 312 574

¹H NMR (CD₃OD) δ (ppm): 11.98 (br s. 1H), 9.03 (br s, 1H), 8.89 (s, 1H),8.20-8.14 (m, 1H), 8.11-8.05 (m, 1H), 7.64-7.57 (m, 1H), 7.53-7.46 (m,1H). MS (m/z): 234.2 (M + H). 313 575

¹H NMR (CD₃OD) δ (ppm): 7.77-7.72 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H),7.37-7.33 (m, 2H), 7.28-7.16 (m, 6H), 5.47 (s, 1H), 4.55 (s, 2H),3.66-3.56 (m, 2H), 3.04-2.94 (m, 2H). MS (m/z): 358.4 (M − H). 314 576

¹H NMR (CD₃OD) δ (ppm): 7.75-7.71 (m, 1H), 7.70-7.65 (m, 1H), 7.53-7.42(m, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.28-7.16 (m, 6H), 5.48 (s, 1H), 4.54(s, 2H), 3.67-3.57 (m, 2H), 3.04-2.93 (m, 2H). MS (m/z): 358.3 (M − H).315 577

2-chloro-N- hydroxy-4-(2- (11-oxodibenzo [b,f][1,4] oxazepin-10(11H)-yl)ethoxy) benzamide ¹H NMR (CD₃OD) δ (ppm): 7.74 (dd, J = 8.0,1.8 Hz, 1H), 7.59 (dd, J = 7.8, 1.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.34-7.20 (m, 6H), 6.95 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.6, 2.4 Hz, 1H),4.51 (br s, 2H), 4.38 (t, J = 5.1 Hz, 2H). MS (m/z): 425.4 (M + H). 316578

3- ((diphenylamino) methyl)-N- hydroxy- benzamide ¹H NMR (DMSO-d₆) δ(ppm): 11.20 (br s, 1H), 9.01 (br s, 1H), 7.74 (s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.27-7.21(m, 4H), 7.06-7.02 (m, 4H), 6.91 (I, J = 7.2 Hz, 2H), 5.04 (s, 2H). MS(m/z): 319.2 (M + H). 319 581

N-hydroxy-2- ((1R,5S)-1-(3- (trifluoromethyl) phenyl)-3-azabicyclo[3.1.0] hexan-3-yl) pyrimidine-5- carboxamide ¹H NMR (CD₃OD) δ(ppm): 8.68 (s, 2H), 7.54 (m, 4H), 4.38 (d, J = 11.2 Hz, 1H), 4.08 (d, J= 11.6 Hz, 1H), 3.80 (m, 2H), 2.19 (m, 1H), 1.24 (m, 1H), 0.93 (t, J =4.8 Hz, 1H). MS (m/z): 363.2 (M − H). 321 583

N-hydroxy-2- ((1R,5S)-1-(4- (trifluoromethyl) phenyl)-3-azabicyclo[3.1.0] hexan-3-yl) pyrimidine-5- carboxamide ¹H NMR (CD₃OD) δ(ppm): 8.68 (s, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H),4.37 (d, J = 10.8 Hz, 1H),4.09 (d, J = 11.6 Hz, 1H), 3.85 (d, J= 11.2Hz, 1H), 3.77 (dd, J = 4 Hz, 11.2 Hz, 1H), 2.22 (m, 1H), 1.26 (m, 1H),0.95 (t, J = 4.8 Hz, 1H). MS (m/z): 363.3 (M − H). 322 584

4-((10H- phenoxazin- 10-yl)methyl)-N- hydroxybenzamide ¹H NMR (MeOD-d4)δ (ppm) 1H: 7.78- 7.73 (m, 2H), 7.46-7.42 (m,2H), 6.77-6.68 (m, 6H),6.45-6.40 (m, 2H), 4.98 (s, 2H). LRMS(ESI): (calc.) 332.4 (found) 331.3(M − H+) 323 585

4-(dibenzo [b,f][1,4]oxazepin- 10(11H)-yl)-N- hydroxybenzamide ¹H NMR(DMSO-d₆) δ (ppm): 10.88 (s, 1H), 8.80 (s, 1H), 7.52 (d, J = 8.8 Hz,2H), 7.39-7.28 (m, 4H), 7.25-7.18 (m, 2H), 7.09-6.99 (m, 2H), 6.74 (d, J= 8.8 Hz, 2H), 4.98 (S, 2H). LRMS(ESI): (calc.) 332.12 (found) 333.4(MH)+ 324 586

(1S,2S)-2-((1R, 5S)-1-(3,4- dichlorophenyl)-3- azabicyclo[3.1.0]hexane-3- carbonyl)-N- hydroxycyclo propane- carboxamide ¹H NMR (CD₃OD)

 (ppm) 1H: [Both diastereomers, 28H total] 7.41-7.46 (m, 4H), 7.16-7.21(m, 2H), 4.21-4.31 (m, 1H), 4.07-4.11 (m, 1H), 3.82-4.02 (m, 4H), 3.55(m, 2H), 2.2-2.29 (m, 2H), 2.10 (m, 1H), 2.03 (m, 1H), 1.95 (m, 2H),1.25-1.35 (m,4H), 1.19 (m, 2H), 0.86 (m, 2H). LRMS(ESI): (calc.) 354.05(found) 353.27 (M)− 325 587

(Z and E)-N- hydroxy-2-(6- oxo-5H-dibenzo [b,e]azepin-11 (6H)-ylidene)acetamide ¹HNMR (DMSO-d₆) δ (ppm): 10.77 (s, 1H), 10.50 and 10.49 (2s,1H), 8.95 (brs, 1H), 7.81 and 7.78 (2d, J = 7.5 Hz, 1H), 6.62 (t, J =7.5 Hz, 0.5H), 7.48 (t, J = 7.1 Hz, 1H), 7.45-7.39 (m, 0.5H), 7.36-7.21(m, 3H), 7.19-7.09 (m, 1.5 H), 7.05 (t, J = 7.5 Hz, 0.5H), 6.07 (s,0.5H), 6.01 (s, 0.5H). LRMS(ESI): (calc.) 280.1 (found) 281.2 (MH)+ 326588

¹HNMR (DMSO-d₆) δ (ppm): 10.67 (s, 1H), 8.91 (s, 1H), 7.36-7.08 (m, 8H),6.05 (s. 1H), 3.55-3.40 (m,2H). LRMS (ESI): (calc.) 313.1 (found) 314.3(MH)+ 327 589

¹H NMR (CD3OD) □ (ppm) 1H: 8.66 (bs, 2H), 7.70 (m, 2H), 7.61 (t, J = 7.6Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 4.22 (d, J = 11.2 Hz, 1H), 4.07 (d, J= 11.6 Hz, 1H), 3.87 (dd, J = 4 Hz, 11.2 Hz, 1H), 3.53 (d, J = 11.6 Hz,1H) 2.09 (m, 1H), 1.27 (m, 1H), 0.908 (t, J = 4.8 Hz, 1H). LRMS(ESI):(calc.) 364.11 (found) 363.26 (M)− 328 590

(E)-3-(4- ((1S,5R)-1-(3,4- dichlorophenyl)-3- azabicyclo[3.1.0] hexan-3-ylsulfonyl) phenyl)-N- hydroxyacrylamide ¹H NMR (CD3OD) □ (ppm) 1H: 7.80(dd, J = 8 Hz, 29.2 Hz, 4H), 7.60 (d, J = 15.6 Hz, 1H), 738 (d, J = 8.4Hz, 1H), 7.30 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 15.6 Hz,1H), 3.86 (d, J = 9.2 Hz, 1H), 3.60 (d, J = 9.2 Hz, 1H), 3.23 (d, J =9.6 Hz, 2H), 1.92 (m, 1H), 0.98 (m, 2H). LRMS(ESI): (calc.) 452.04(found) 451.27 (M)−

Compositions

In a second aspect, the invention provides compositions comprising aninhibitor of histone deacetylase according to the invention and apharmaceutically acceptable carrier, excipient, or diluent. Compounds ofthe invention may be formulated by any method known in the art and maybe prepared for administration by any route, including, withoutlimitation, parenteral, oral, sublingual, transdermal, topical,intranasal, intratracheal, or intrarectal. In certain preferredembodiments, compounds of the invention are administered intravenouslyin a hospital setting. In certain other preferred embodiments,administration may preferably be by the oral route. The compositions maybe in any form, including but not limited to, liquid solutions orsuspensions; for oral administration, formulations may be in the form oftablets or capsules; and for intranasal formulations, in the form ofpowders, nasal drops or aerosols. The compositions of the invention maybe administered systemically or locally.

The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, or other materials well known in theart. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term “pharmaceutically acceptable salts” is intendedto mean salts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate). As used herein, the term “salt” isalso meant to encompass complexes, such as with an alkaline metal or analkaline earth metal.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver an inhibitioneffective amount without causing serious toxic effects. The effectivedosage range of the pharmaceutically acceptable derivatives can becalculated based on the weight of the parent compound to be delivered.If the derivative exhibits activity in itself, the effective dosage canbe estimated as above using the weight of the derivative, or by othermeans known to those skilled in the art.

In certain preferred embodiments of the second aspect of the invention,the composition further comprises an antisense oligonucleotide thatinhibits the expression of a histone deacetylase gene. The combined useof a nucleic acid level inhibitor (e.g., antisense oligonucleotide) anda protein level inhibitor (i.e., inhibitor of histone deacetylase enzymeactivity) results in an improved inhibitory effect, thereby reducing theamounts of the inhibitors required to obtain a given inhibitory effectas compared to the amounts necessary when either is used individually.The antisense oligonucleotide according to this aspect of the inventionis complementary to regions of RNA or double-stranded DNA that encodeone or more of, for example, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5,HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-11 (see e.g., GenBankAccession Number U50079 for HDAC-1, GenBank Accession Number U31814 forHDAC-2, and GenBank Accession Number U75697 for HDAC-3).

Inhibition of Histone Deacetylase

In a third aspect, the present invention provides a method of inhibitinghistone deacetylase, comprising contacting the histone deacetylase withan inhibition effective amount of an inhibitor of histone deacetylase ofthe present invention.

In another embodiment of the third aspect, the invention provides amethod of inhibiting histone deacetylase in a cell, comprisingcontacting the cell in which inhibition of histone deacetylase isdesired with an inhibition effective amount of an inhibitor of histonedeacetylase, or composition thereof, according to the present invention.

Because compounds of the invention inhibit histone deacetylase, they areuseful research tools for in vitro study histone deacetylases and theirrole in biological processes.

Measurement of the enzymatic activity of a histone deacetylase can beachieved using known methodologies. For Example, Yoshida et al., J.Biol. Chem., 265: 17174-17179 (1990), describes the assessment ofhistone deacetylase enzymatic activity by the detection of acetylatedhistones in trichostatin A treated cells. Taunton et al., Science, 272:408-411 (1996), similarly describes methods to measure histonedeacetylase enzymatic activity using endogenous and recombinant HDAC-1.

In some preferred embodiments, the histone deacetylase inhibitorinteracts with and reduces the activity of all histone deacetylases in acell. In some other preferred embodiments according to this aspect ofthe invention, the histone deacetylase inhibitor interacts with andreduces the activity of fewer than all histone deacetylases in the cell.In certain preferred embodiments, the inhibitor interacts with andreduces the activity of one histone deacetylase (e.g., HDAC-1), but doesnot interact with or reduce the activities of other histone deacetylases(e.g., HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9,HDAC-10 and HDAC-11).

The term “inhibition effective amount” is meant to denote a dosagesufficient to cause inhibition of histone deacetylase activity in acell, which cell can be in a multicellular organism. The multicellularorganism can be a plant or an animal, preferably a mammal, morepreferably a human. If in a multicellular organism, the method accordingto this aspect of the invention comprises administering to the organisma compound or composition according to the present invention.Administration may be by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain particularly preferredembodiments, compounds of the invention are administered intravenouslyin a hospital setting. In certain other preferred embodiments,administration may preferably be by the oral route.

In certain preferred embodiments of the third aspect of the invention,the method further comprises contacting a histone deacetylase enzyme ora cell expressing histone deacetylase activity with an antisenseoligonucleotide that inhibits the expression of a histone deacetylasegene. The combined use of a nucleic acid level inhibitor (e.g.,antisense oligonucleotide) and a protein level inhibitor (i.e.,inhibitor of histone deacetylase enzyme activity) results in an improvedinhibitory effect, thereby reducing the amounts of the inhibitorsrequired to obtain a given inhibitory effect as compared to the amountsnecessary when either is used individually. The antisenseoligonucleotides according to this aspect of the invention arecomplementary to regions of RNA or double-stranded DNA that encode, forexample, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8,HDAC-9, HDAC-10 and HDAC-11 (see e.g., GenBank Accession Number U50079for HDAC-1, GenBank Accession Number U31814 for HDAC-2, and GenBankAccession Number U75697 for HDAC-3).

For purposes of the invention, the term “oligonucleotide” includespolymers of two or more deoxyribonucleosides, ribonucleosides, or2′-substituted ribonucleoside residues, or any combination thereof.Preferably, such oligonucleotides have from about 6 to about 100nucleoside residues, more preferably from about 8 to about 50 nucleosideresidues, and most preferably from about 12 to about 30 nucleosideresidues. The nucleoside residues may be coupled to each other by any ofthe numerous known internucleoside linkages. Such internucleosidelinkages include without limitation phosphorothioate,phosphorodithioate, alkylphosphonate, alkylphosphonothioate,phosphotriester, phosphoramidate, siloxane, carbonate,carboxymethylester, acetamidate, carbamate, thioether, bridgedphosphoramidate, bridged methylene phosphonate, bridged phosphorothioateand sulfone internucleoside linkages. In certain preferred embodiments,these internucleoside linkages may be phosphodiester, phosphotriester,phosphorothioate, or phosphoramidate linkages, or combinations thereof.The term oligonucleotide also encompasses such polymers havingchemically modified bases or sugars and/or having additionalsubstituents, including without limitation lipophilic groups,intercalating agents, diamines and adamantane.

For purposes of the invention the term “2′-substituted ribonucleoside”includes ribonucleosides in which the hydroxyl group at the 2′ positionof the pentose moiety is substituted to produce a 2′-O-substitutedribonucleoside. Preferably, such substitution is with a lower alkylgroup containing 1-6 saturated or unsaturated carbon atoms, or with anaryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl orallyl group may be unsubstituted or may be substituted, e.g., with halo,hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl,carbalkoxyl, or amino groups. The term “2′-substituted ribonucleoside”also includes ribonucleosides in which the 2′-hydroxyl group is replacedwith an amino group or with a halo group, preferably fluoro.

Particularly preferred antisense oligonucleotides utilized in thisaspect of the invention include chimeric oligonucleotides and hybridoligonucleotides.

For purposes of the invention, a “chimeric oligonucleotide” refers to anoligonucleotide having more than one type of internucleoside linkage.One preferred example of such a chimeric oligonucleotide is a chimericoligonucleotide comprising a phosphorothioate, phosphodiester orphosphorodithioate region, preferably comprising from about 2 to about12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region(see e.g., Pederson et al. U.S. Pat. Nos. 5,635,377 and 5,366,878).Preferably, such chimeric oligonucleotides contain at least threeconsecutive internucleoside linkages selected from phosphodiester andphosphorothioate linkages, or combinations thereof.

For purposes of the invention, a “hybrid oligonucleotide” refers to anoligonucleotide having more than one type of nucleoside. One preferredexample of such a hybrid oligonucleotide comprises a ribonucleotide or2′-substituted ribonucleotide region, preferably comprising from about 2to about 12 2′-substituted nucleotides, and a deoxyribonucleotideregion. Preferably, such a hybrid oligonucleotide contains at leastthree consecutive deoxyribonucleosides and also containsribonucleosides, 2′-substituted ribonucleosides, preferably2′-O-substituted ribonucleosides, or combinations thereof (see e.g.,Metelev and Agrawal, U.S. Pat. No. 5,652,355).

The exact nucleotide sequence and chemical structure of an antisenseoligonucleotide utilized in the invention can be varied, so long as theoligonucleotide retains its ability to inhibit expression of the gene ofinterest. This is readily determined by testing whether the particularantisense oligonucleotide is active. Useful assays for this purposeinclude quantitating the mRNA encoding a product of the gene, a Westernblotting analysis assay for the product of the gene, an activity assayfor an enzymatically active gene product, or a soft agar growth assay,or a reporter gene construct assay, or an in vivo tumor growth assay,all of which are known in the art, or are as described in detail in thisspecification or in, for example, Ramchandani et al. (1997) Proc. Natl.Acad. Sci. USA 94: 684-689.

Antisense oligonucleotides utilized in the invention may conveniently besynthesized on a suitable solid support using well known chemicalapproaches, including H-phosphonate chemistry, phosphoramiditechemistry, or a combination of H-phosphonate chemistry andphosphoramidite chemistry (i.e., H-phosphonate chemistry for some cyclesand phosphoramidite chemistry for other cycles). Suitable solid supportsinclude any of the standard solid supports used for solid phaseoligonucleotide synthesis, such as controlled-pore glass (CPG) (see,e.g., Pon, R. T. (1993) Methods in Molec. Biol. 20: 465-496).

Particularly preferred oligonucleotides have nucleotide sequences offrom about 13 to about 35 nucleotides which include the nucleotidesequences shown in Table 44. Yet additional particularly preferredoligonucleotides have nucleotide sequences of from about 15 to about 26nucleotides which include the nucleotide sequences shown in Table 7.

TABLE 7 Accession Nucleotide position Oligo Target Number PositionSequence within Gene Seq ID No. HDAC1 AS1 Human HDAC1 U50079 1585-16045′-GAAACGTGAGGGACTCAGCA-3′ 3′-UTR Seq ID No: 1 HDAC1 AS2 Human HDAC1U50079 1565-1584 5′-GGAAGCCAGAGCTGGAGAGG-3′ 3′-UTR Seq ID No: 2 HDAC2 ASHuman HDAC2 U31814 1643-1622 5′-GCTGAGCTGTTCTGATTTGG-3′ 3′-UTRSeq ID No: 3 HDAC3 AS Human HDAC3 AF039703 1276-12955′-CGCTTTCCTTGTCATTGACA-3′ 3′-UTR Seq ID No: 4 HDAC4 AS1 Human HDAC4AB006626  514-33 5′-GCTGCCTGCCGTGCCCACCC-3′ 5′-UTR Seq ID No: 5HDAC4 AS2 Human HDAC4 AB006626 7710-29 5′-TACAGTCCATGCAACCTCCA-3′ 3′-UTRSeq ID No: 6 HDAC5 AS Human HDAC5 AF039691 2663-26825′-CTTCGGTCTCACCTGCTTGG-3′ 3′-UTR Seq ID No: 7 HDAC6 AS Human HDAC6AJ011972 3791-3810 5′-CAGGCTGGAATGAGCTACAG-3′ 3′-UTR Seq ID No: 8HDAC7 AS Human HDAC7 AF239243 2896-2915 5′-CTTCAGCCAGGATGCCCACA-3′3′-UTR Seq ID No: 9 HDAC8 AS1 Human HDAC8 AF230097 51-705′-CTCCGGCTCCTCCATCTTCC-3′ 5'-UTR Seq ID No: 10 HDAC8 AS2 Human HDAC8AF230097 1328-1347 5′-AGCCAGCTGCCACTTGATGC-3′ 3'-UTR Seq ID No: 11

In certain preferred embodiments of the invention, the antisenseoligonucleotide and the HDAC inhibitor of the present invention areadministered separately to a mammal, preferably a human. For example,the antisense oligonucleotide may be administered to the mammal prior toadministration to the mammal of the HDAC inhibitor of the presentinvention. The mammal may receive one or more dosages of antisenseoligonucleotide prior to receiving one or more dosages of the HDACinhibitor of the present invention.

In another embodiment, the HDAC inhibitor of the present invention maybe administered to the mammal prior to administration of the antisenseoligonucleotide. The mammal may receive one or more dosages of the HDACinhibitor of the present invention prior to receiving one or moredosages of antisense oligonucleotide.

In certain other preferred embodiments of the present invention, theHDAC inhibitor of the present invention may be administered togetherwith another HDAC inhibitor known in the art or which will bediscovered. Administration of such HDAC inhibitor(s) may be donesequentially or concurrently. In certain preferred embodiments of thepresent invention the composition comprises an HDAC inhibitor of thepresent invention and/or an antisense oligonucleotide and/or anotherHDAC inhibitor known in the art or which will be discovered. The activeingredients of such compositions preferably act synergistically toproduce a therapeutic effect.

In certain embodiments, the known HDAC inhibitor is selected from thegroup consisting of, but not limited to, trichostatin A, depudecin,trapoxin, suberoylanilide hydroxamic acid, FR901228, MS-27-275, CI-994sodim butyrate, MGCD0103, and those compounds found in WO 2003/024448,WO 2004/069823, WO 2001/038322, U.S. Pat. No. 6,541,661, WO 01/70675, WO2004/035525 and WO 2005/030705.

The following examples are intended to further illustrate certainpreferred embodiments of the invention, and are not intended to limitthe scope of the invention.

ASSAY EXAMPLES Assay Example 1 Inhibition of Histone DeacetylaseEnzymatic Activity

The following protocol is used to assay the compounds of the invention.In the assay, the buffer used is 25 mM HEPES, pH 8.0, 137 mM NaCl, 2.7mM KCl, 1 mM MgCl₂ and the substrate is Boc-Lys(Ac)-AMC in a 50 mM stocksolution in DMSO. The enzyme stock solution is 4.08 μg/mL in buffer.

The compounds are pre-incubated (2 μl in DMSO diluted to 13 μl in bufferfor transfer to assay plate) with enzyme (20 μl of 4.08 μg/ml) for 10minutes at room temperature (35 μl pre-incubation volume). The mixtureis pre-incubated for 5 minutes at room temperature. The reaction isstarted by bringing the temperature to 37° C. and adding 16 μlsubstrate. Total reaction volume is 50 μl. The reaction is stopped after20 minutes by addition of 50 μl developer, prepared as directed byBiomol (Fluor-de-Lys developer, Cat. #KI-105). A plate is incubated inthe dark for 10 minutes at room temperature before reading (λ_(Ex)=360nm, λ_(Em)=470 nm, Cutoff filter at 435 nm).

All compounds exemplified have an IC₅₀ value less than or equal to 10 μMagainst one or more of HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6,HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-11. Tables 8, 9 and 10 showselected examples. In the Tables 8, 9 and 10, A≦0.050 M; 0.05 M<B≦0.1μM; 0.1 μM<C≦1 μM; and 1 μM<D≦10 μM.

Assay Example 2 Whole-Cell Histone Deacetylase (HDAC) Inhibition Assayin Primary Mouse Cortical Cultures

Primary neocortical cultures are established through the dissection ofthe neocortex from E17 embryos harvested from time-pregnant Balb/C mice.Following dissection, the neocortical tissue specimens undergo digestionby incubation at 37° C. for 10 minutes in dissection medium (1×HBSS/10mM HEPES/1 mM Sodium Pyruvate) supplemented with (0.25%) Trypsin and(0.1%) DNase I. Digested tissue is washed and resuspended in platingmedium (NeuroBasal/10% HS/0.5 mM L-Glutamine (Invitrogen Corporation))for trituration. Additional plating medium is added, and the contentsare passed over a 70 um cell-strainer. The cell-density is quantifiedusing a hemacytometer, and dilutions are made to allow for the platingof 50000 cells/well/100 uL in 96-well PDL-coated plates. Plates areincubated for 4-5 hours in 37° C./5% CO₂-incubator, after which time theentire volume is exchanged to feeding medium (NeuroBasal/2% B-27Serum-free supplement/0.5 mM L-Glutamine/1% Penicillin-Streptomycin(Invitrogen Corporation)). The cultures undergo two 50% fresh feedingmedium exchanges at 3 days in vitro (DIV3), and again at DIV7.

Compounds for testing are resuspended in dimethyl sulphoxide (DMSO), andfurther diluted in DMSO for a ten-point dose-response curve, withappropriate controls. Each master plate is assayed in triplicate. 3.5uL/well of the master dilution plate is transferred to a 96-wellround-bottom daughter plate, to which 175 uL/well of warmed feedingmedium is added and thoroughly mixed. Three DIV9 culture plates areleveled to 50 uL/well, onto which each has overlaid 50 uL/well of thediluted daughter plate. The plates are returned to the 37° C./5%CO₂-incubator for 16-18 hours.

The next step of the assay involves the exposure of a HDAC colorimetricsubstrate, comprising an acetylated lysine side chain, to thecompound-treated neuronal cultures. Based on the ability of the compoundto inhibit HDAC activity in the neuronal cultures, the substrate isdeacetylated by HDACs, and subsequently sensitized. A 7.5 mMBOC-Lys(Ac)-AMC (Bachem Bioscience, Inc.) substrate solution is preparedby making a 1:1 dilution of 15 mM BOC-Lys(Ac)-AMC with HDAC Assay Buffer(25 mM Tris-Cl/137 mM NaCl/2.7 mM KCl/mM MgCl₂). Compound-incubatedculture plates are again leveled to 50 uL/well and 2 uL/well of 7.5 mMBOC-Lys (Ac)-AMC substrate is added and thoroughly mixed. Plates arereturned to the 37° C./5% CO₂-incubator for 1 hour.

The final addition to the culture plates entails treatment with a Fluorde LyS™-based developer (BIOMOL Research Laboratories, Inc.) to producea fluorophore, which is analyzed using a spectrophotometer. Thedeveloper solution (1× Fluor de Lys™/1% NP-40/1 uM TSA in HDAC BufferSolution) is prepared, and 50 uL/well is added to each of the wells ofthe culture plates. Trichostatin A is typically added as an “inhibitorstop” for class I and II HDACs. The plates are returned to the 37° C./5%CO₂-incubator for 10-15 minutes, after which time, they are removed andset in the dark at room temperature for 5-10 minutes. The plates areread, and the results used to determine the percent HDAC activity ofeach compound compared to DMSO controls, and subsequently, used tocalculate the corresponding IC₅₀ values.

Assay Example 3 Ex Vivo Histone Acetylation Analysis Via WesternBlotting of Mouse Liver and Striatal Tissues from Mice Orally-Dosed withHistone Deacetylase (HDAC) Inhibitors

Pre-weighed liver and striatal specimens are transferred from −80° C. towet-ice to be processed for tissue-homogenization. For the liverspecimens, a 20-fold excess of chilled 1×XT LDS (Bio-Rad Laboratories,Inc.) sample buffer is added over the weight of each individual liversample, and a 10-fold excess over the weight of the striatal samples.After adding 1.0 mm Zirconia-Silica beads (BioSpec Products, Inc.) toeach sample, the tubes are loaded into the Mini-Beadbeater™ (BioSpecProducts, Inc.), the liver samples are homogenized for 4 minutes, andthe striatal samples for 3 minutes.

Rescued homogenates are then heated at 95° C. for 10-15 minutes,vortexed briefly, and centrifuged at 13200 rpm for 4 minutes. Samplesare diluted 1:10, and 20×XT Reducing agent (Bio-Rad Laboratories, Inc.)is added in preparation for loading.

15 uL of each diluted sample is loaded in CRITERION™ 4-12% Bis-Tris gels(Bio-Rad Laboratories, Inc.) and run at 150V (constant) in a 1×XT MESbuffer system (Bio-Rad Laboratories, Inc.) until the dye-front reachesthe bottom.

Immobilon-FL PVDF-membranes (Millipore Corporation) are brieflyactivated in Methanol, hydrated in diH₂O, and then equilibrated inchilled 1× Tris-Glycine transfer buffer (Bio-Rad Laboratories, Inc.)supplemented with 10% Methanol until the transfer-sandwiches are readyto be assembled. Gels are removed from the cartridges and equilibratedfor 15 minutes in chilled transfer buffer. Transfer-sandwiches areassembled, loaded into the CRITERION™ Blotter System, and transferredfor 40 minutes at 100V (constant).

PVDF-membranes are removed, rinsed briefly in diH₂O, and then blockedfor 1 hour in 1:1 dilution (in PBS) of Odyssey Blocking Buffer solution(LI-COR Bioscience, Inc.).

Primary antibody solution is prepared as follows: Into 40 mL of 1:1diluted Odyssey Blocking Buffer is added 4 uL of anti-Actin (AC-15)antibody (Sigma-Aldrich Co.), 8 uL of anti-Acetylated H2A antibody(Millipore Corporation) and 20 uL of anti-Acetylated H4 antibody(Millipore Corporation). PVDF membranes are incubated in primaryantibody solution overnight at 4° C.

Membranes are washed 4×5 minutes in TBS-T (Sigma-Aldrich Co.). Secondaryantibody solution is prepared as follows: Into 40 mL of TBS-T solution,supplemented with 0.02% SDS (Sigma-Aldrich Co.), is added 4 uL of goatanti-rabbit IRDye800 antibody (Rockland, Inc.) and 4 uL of goatanti-mouse AlexaFluor 680 antibody (Invitrogen Corporation). PVDFmembranes are incubated in secondary antibody solution, protected fromlight, for 1 h at room temperature. Membranes are washed 4×5 minutes inTBS-T, followed by 2×2 minute washes in PBS solution.

PVDF membranes are scanned using LI-COR/Odyssey Infrared Imaging System.Induced acetylation of Histone 2A or Histone 4 is calculated for eachsample by dividing the integrated intensity of the designated acetylatedhistone band by the integrated intensity of the actin band from the samesample, correcting for loading variability. The individually normalizedsample values from each treatment group, assayed in triplicate, are thenaveraged and plotted as a relative Histone 2A or Histone 4 acetylationlevel.

Assay Example 3 Whole-Cell Histone Deacetylase (HDAC) Inhibition Assayin Normal Human Astrocyte Cultures

Normal human astrocyte cultures (Lonza, Inc.) are passaged usingstandard passaging techniques. Pelleted cells are resuspended inAstrocyte Growth Medium (Astrocyte Basal Medium/3% FBS/1%L-Glutamine/0.1% Ascorbic acid/0.1% rhEGF/0.25% Insulin/0.1% GentamycinSulfate-Amphotericin; (Lonza, Inc.)). The cell density is quantifiedusing a hemacytometer, and dilutions are made to allow for the platingof 10000 cells/well/100 uL into 96-well flat-bottomed TC-treated plates.The cultures plates are incubated at 37° C./5% CO₂ overnight.

Compounds for testing are resuspended in dimethyl sulphoxide (DMSO), andfurther diluted in DMSO for a ten-point dose-response curve, withappropriate controls. Each master plate is assayed in triplicate. 3.5uL/well of the master dilution plate is transferred to a 96-wellround-bottom daughter plate, to which 175 uL/well of warmed AstrocyteGrowth Medium is added and thoroughly mixed. Three culture plates areleveled to 50 uL/well, onto which each has overlaid 50 uL/well of thediluted daughter plate. The plates are returned to the 37° C./5%CO₂-incubator for 16-18 hours.

The next step of the assay involves the exposure of a HDAC colorimetricsubstrate, comprising an acetylated lysine side chain, to thecompound-treated human astrocyte cultures. Based on the ability of thecompound to inhibit HDAC activity in the human astrocyte cultures, thesubstrate is deacetylated by HDACs, and subsequently sensitized. A 7.5mM BOC-Lys(Ac)-AMC (Bachem Bioscience, Inc.) substrate solution isprepared by making a 1:1 dilution of 15 mM BOC-Lys(Ac)-AMC with HDACAssay Buffer (25 mM Tris-Cl/137 mM NaCl/2.7 mM KCl/1 mM MgCl₂).Compound-incubated culture plates are again leveled to 50 uL/well and 2uL/well of 7.5 mM BOC-Lys (Ac)-AMC substrate is added and thoroughlymixed. Plates are returned to the 37° C./5% CO₂-incubator for 1 hour.

The final addition to the culture plates entails treatment with a Fluorde Lys™-based developer (BIOMOL Research Laboratories, Inc.) to producea fluorophore, which is analyzed using a spectrophotometer. Thedeveloper solution (1× Fluor de Lys™/1% NP-40/1 uM TSA in HDAC BufferSolution) is prepared, and 50 uL/well is added to each of the wells ofthe culture plates. Trichostatin A is typically added as an “inhibitorstop” for class I and II HDACs. The plates are returned to the 37° C./5%CO₂-incubator for 10-15 minutes, after which time, they are removed andset in the dark at room temperature for 5-10 minutes. The plates areread, and the results are used to determine the percent HDAC activity ofeach compound compared to DMSO controls, and subsequently, used tocalculate the corresponding IC50 values.

The activity (IC₅₀ μM) of selected compounds in the above-mentionedneuronal cell based assay are shown in Tables 8, 9 and 10. In the Tables8, 9 and 10, W≦1 μM; 1<X≦5 μM; 5<Y≦15 μM; and 15<Z.

TABLE 8 HDAC Inhibtion (IC₅₀ μM) WC mouse HDAC cortical Compound NameEnzyme neurons(E)-2-(4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)piperazin-1-yl)- A YN-hydroxypyrimidine-5-carboxamide(Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide A W(Z)-4-(dibenzo[b,f][1,4]thiazepin-11-yl)-N-hydroxybenzamide C —4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N- A X hydroxybenzamideN-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin- C Y11-yl)benzamide (Z)-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N- BX hydroxybenzamide (Z)-4-(benzo[b]pyrido[3,2-f][1,4]oxazepin-5-yl)-N- BX hydroxybenzamide (Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N- AX hydroxybenzamide(Z)-N-hydroxy-4-(2-methoxydibenzo[b,f][1,4]oxazepin-11- C Y yl)benzamide(Z)-4-(benzo[b]pyrido[4,3-f][1,4]oxazepin-5-)-N- C W hydroxybenzamide(Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11- n/d Zyl)-N-hydroxybenzamide(Z)-N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11- C Yyl)benzamide (Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-2-fluoro-N- C Yhydroxybenzamide (Z)-5-(4-(hydroxycarbamoyl)phenyl)benzo[b]pyrido[4,3- CY f][1,4]oxazepine 2-oxide(Z)-N-hydroxy-4-(3-methoxydibenzo[b,f][1,4]oxazepin-11- C X yl)benzamide(Z)-3-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide C Z(Z)-N-hydroxy-4-(8-methyldibenzo[b,f][1,4]oxazepin-11- B X yl)benzamide(Z)-N-hydroxy-4-(4-methoxydibenzo[b,f][1,4]oxazepin-11- B X yl)benzamide

D Y (Z)-4-(9-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N- B Xhydroxybenzamide(Z)-N-hydroxy-4-(7-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin- C Z11-yl)benzamide (Z)-4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N- C Yhydroxybenzamide (Z)-4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N- A Yhydroxybenzamide

C X (E)-N-hydroxy-11-(4-methylpiperazin-1- C n/dyl)dibenzo[b,f][1,4]oxazepine-8-carboxamide(Z)-4-(8-cyanodibenz[b,f][1,4]oxazepin-11-yl)-N- B X hydroxybenzamide(Z)-N-hydroxy-4-(4-methyldibenzo[b,f][1,4]oxazepin-11- B X yl)benzamide(Z)-N-hydroxy-4-(3-methyldibenzo[b,f][1,4]oxazepin-11- A X yl)benzamide(Z)-N-hydroxy-11-(pyridin-4-yl)dibenzo[b,f][1,4]oxazepine-8- C n/dcarboxamide (Z)-4-(benzo[b]thieno[2,3-f][1,4]oxazepin-10-yl)-N- A Xhydroxybenzamide (Z)-4-(3-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N- C Zhydroxybenzamide (Z)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N- C Yhydroxybenzamide(Z)-N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11- B Zyl)benzamide (Z)-4-(6-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N- B Yhydroxybenzamide (Z)-4-(7-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N- A Yhydroxybenzamide (Z)-N-hydroxy-4-(4-hydroxydibenzo[b,f][1,4]oxazepin-11-B W yl)benzamide (Z)-N-hydroxy-4-(1-methoxydibenzo[b,f][1,4]oxazepin-11-C Z yl)benzamide(Z)-N-hydroxy-4-(4-(2-methoxyethoxy)dibenzo[b,f][1,4]oxazepin- A X11-yl)benzamide(E)-N-hydroxy-4-(11-morpholinodibenzo[b,f][1,4]oxazepin-2- A Zyl)benzamide (Z)-4-(1-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N- A Yhydroxybenzamide (Z)-N-hydroxy-4-(2-(trifluoromethyl)benzo[f]pyrido[2,3-B Y b][1,4]oxazepin-6-yl)benzamide(Z)-4-(11-cyclopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5- A Wyl)-N-hydroxybenzamide(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N- C Xhydroxybenzamide(Z)-4-(5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide C X(Z)-N-hydroxy-4-(4-(2- A Wmorpholinoethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(Z)-4-(benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)-N- A X hydroxybenzamide(Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N- A Xhydroxybenzamide(Z)-N-hydroxy-4-(4-(methylthio)dibenzo[b,f][1,4]oxazepin-11- A Xyl)benzamide(Z)-N-hydroxy-4-(4-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11- A Zyl)benzamide(Z)-N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11- B Xyl)benzamide (Z)-4-(5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-yl)-N- A Xhydroxybenzamide(Z)-N-hydroxy-4-(4-(methylsulfonyl)dibenzo[b,f][1,4]oxazepin-11- A Xyl)benzamide (E)-4-((dibenzo[b,f][1,4]oxazepin-11-ylamino)methyl)-N- A Whydroxybenzamide (Z)-N-hydroxy-4-(4-methoxy-8- C Y(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide(Z)-N-hydroxy-4-(3-morpholinodibenzo[b,f][1,4]oxazepin-11- C Yyl)benzamide (Z)-N-hydroxy-4-(4-propyldibenzo[b,f][1,4]oxazepin-11- C Zyl)benzamide(Z)-N-hydroxy-4-(4-(trifluoromethoxy)dibenzo[b,f][1,4]oxazepin- C Z11-yl)benzamide (Z)-N-hydroxy-4-(6-methyldibenzo[b,f][1,4]oxazepin-11- CY yl)benzamide (E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N- D Yhydroxybenzamide(E)-6-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxynicotinamide C Y(E)-5-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxyfuran-2- D Zcarboxamide

C Y (E)-5-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxythiophene-2- A Xcarboxamide (Z)-4-(5-ethyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N- B Xhydroxybenzamide(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N- D n/dhydroxy-N-methylbenzamide(Z)-N-hydroxy-4-(5-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11- A Wyl)benzamide (E)-4((5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11- C Yylamino)methyl)-N-hydroxybenzamide(Z)-4-(4-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N- C Y hydroxybenzamide(Z)-N-hydroxy-4-(5-(2-methoxyethyl)-5H- C Xdibenzo[b,e][1,4]diazepin-11-yl)benzamide(E)-4-(2-(dibenzo[b,f][1,4]oxazepin-11-ylamino)ethyl)-N- C Yhydroxybenzamide(Z)-4-(11-ethyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N- A Whydroxybenzamide(Z)-4-(5-cyclopropyl-2-fluoro-5H-dibenzo[b,e][1,4]diazepin-11-yl)- B XN-hydroxybenzamide (Z)-N-hydroxy-4-(11-isopropyl-11H-benzo[b]pyrido[2,3-A W e][1,4]diazepin-5-yl)benzamide(Z)-4-(benzo[f]thieno[2,3-b][1,4]oxazepin-5-yl)-N- C X hydroxybenzamide(Z)-6-(4-(dibenzo[b,f][1,4]oxazepin-11-yl)benzamidooxy)-3,4,5- — Ztrihydroxytetrahydro-2H-pyran-2-carboxylic acid(Z)-N-hydroxy-4-(11-(3-morpholinopropyl)-11H- C Xbenzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide(Z)-N-hydroxy-4-(11-(2-morpholinoethyl)-11H- B Xbenzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide(Z)-4-(11-(cyclopropylmethyl)-11H-benzo[b]pyrido[2,3- D n/de][1,4]diazepin-5-yl)-N-hydroxybenzamide(Z)-N-hydroxy-4-(5-(2-morpholinoethyl)-5H- C n/ddibenzo[b,e][1,4]diazepin-11-yl)benzamide

TABLE 9 HDAC Inhibition (IC₅₀ μM) WC mouse HDAC cortical Compound NameEnzyme neurons2-((1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- C Xhydroxypyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) A Wpyrimidine-5-carboxamide2-((1S,4S)-5-benzhydryl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- A Xhydroxypyrimidine-5-carboxamide2-((1S,4S)-5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- A WN-hydroxypyrimidine-5-carboxamide (1S,4S)-tert-butyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptane-2-carboxylate2-((1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.21]heptan-2-yl)- A WN-hydroxypyrimidine-5-carboxamide2-((1S,4S)-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- B WN-hydroxypyrimidine-5-carboxamide2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- C Yhydroxypyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-o-tolyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) B Xpyrimidine-5-carboxamide2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-hydroxypyrimidine-5- C XcarboxamideN-hydroxy-2-((1S,4S)-5-phenyl-2,5-diazabicyclo[2.2.1]heptan-2- B Wyl)pyrimidine-5-carboxamide2-((1S,4S)-5-benzoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- A Whydroxypyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide2-((1S,4S)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-2,5- A Xdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamideN-hydroxy-2-((1S,4S)-5-(2-(trifluoromethyl)phenyl)-2,5- C Xdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-(4-(trifluoromethyl)phenyl)-2,5- A Xdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide2-((1S,4S)-5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide2-((1S,4S)-5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamideN-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)benzoyl)-2,5- B Xdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide2-((1S,4S)-5-(benzo[d][1,3]dioxol-5-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide2-((1S,4S)-5-(cyclohexanecarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-n/d X N-hydroxypyrimidine-5-carboxamide2-((1S,4S)-5-(2,2-diphenylacetyl)-2,5-diazabicyclo[2.2.1]heptan-2- B Xyl)-N-hydroxypyrimidine-5-carboxamideN-hydroxy-4-((1S,4S)-5-p-tolyl-2,5-diazabicyclo[2.2.l]heptan-2- C Xyl)benzamide N-hydroxy-2-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5- A Xdiazabicyclo[2.2.1]heptan-2-yl)thiazole-5-carboxamide (1S,4S)-benzyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptane-2-carboxylate (1S,4S)-isobutyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptane-2-carboxylateN-hydroxy-2-((1S,4S)-5-(3-(trifluoromethoxy)phenyl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide2-((1S,4S)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2,5- A Xdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamideN-hydroxy-2-((1S,4S)-5-(3-(trifluoromethylthio)phenyl)-2,5- A Xdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-(2-(trifluoromethyl)quinolin-4-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide2-((1S,4S)-5-(3-(difluoromethoxy)phenyl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamideN-hydroxy-2-((1S,4S)-5-(6-(trifluoromethyl)pyridin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide(1S,4S)-cyclopentyl 5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptane-2-carboxylate2-((1S,4S)-5-(benzo[c][1,2,5]oxadiazol-4-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamideN-hydroxy-2-((1S,4S)-5-(5-(trifluoromethyl)pyridin-3-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1R,4R)-5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2- A Wyl)pyrimidine-5-carboxamide (1S,4S)-isopropyl5-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptane-2-carboxylate (1S,4S)-pyridin-3-ylmethyl5-(5-(hydroxycarbamoyl)pyrimidin-2- A Wyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(1S,4S)-cyclopropylmethyl 5-(5-(hydroxycarbamoyl)pyrimidin-2- A Wyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(1S,4S)-tetrahydro-2H-pyran-4-yl 5-(5- A W(hydroxycarbamoyl)pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 2-((1S,4S)-5-(3,5-bis(trifluoromethyl)phenyl)-2,5- A Xdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide2-((1S,4S)-5-(benzo[d]isoxazol-3-yl)-2,5-diazabicyclo[2.2.1]heptan- A W2-yl)-N-hydroxypyrimidine-5-carboxamide2-((1S,4S)-5-(3-(dimethylcarbamoyl)phenyl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamide2-((1S,4S)-5-(3-((dimethylamino)methyl)phenyl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)-N-hydroxypyrimidine-5- carboxamideN-hydroxy-2-((1S,4S)-5-(3-methoxyphenyl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2- A Wyl)pyrimidine-5-carboxamideN-hydroxy-6-(5-p-tolyl-2,5-diazabicyclo[2.2.1]heptan-2- A Wyl)nicotinamide N-hydroxy-5-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5-C Y diazabicyclo[2.2.1]heptan-2-yl)pyrazine-2-carboxamide2-fluoro-N-hydroxy-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5- C Ydiazabicyclo[2.2.1]heptan-2-yl)benzamideN-hydroxy-2-((1S,4S)-5-(pyrrolidine-1-carbonyl)-2,5- B Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1S,4S)-5-(4-(trifluoromethyl)pyrimidin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-6-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5- C Ydiazabicyclo[2.2.1]heptan-2-yl)pyridazine-3-carboxamideN-hydroxy-2-(7-(4-(trifluoromethyl)pyridin-2-yl)-3,7- C Zdiazabicyclo[3.3.1]nonan-3-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5- A Wdiazabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2- B Wyl)pyrimidine-5-carboxamide

A W 2-(5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N- A Whydroxypyrimidine-5-carboxamideN-hydroxy-4-(5-(3-methoxyphenyl)-2,5-diazabicyclo[2.2.1]heptan- C X2-yl)benzamide N-hydroxy-4-(5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2- CX yl)benzamide N-hydroxy-4-((1S,4S)-5-(3-(trifluoromethyl)phenyl)-2,5- CX diazabicyclo[2.2.1]heptan-2-yl)benzamideN-hydroxy-4-((1S,4S)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5- C Xdiazabicyclo[2.2.1]heptan-2-yl)benzamide4-((1S,4S)-5-(3-cyanophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- C XN-hydroxybenzamideN-hydroxy-4-((1R,4R)-5-m-tolyl-2,5-diazabicyclo[2.2.1]heptan-2- C Xyl)benzamideN-hydroxy-4-((1R,4R)-5-(4-(trifluoromethyl)pyridin-2-yl)-2,5- D Ydiazabicyclo[2.2.1]benzamideN-hydroxy-4-((1S,4S)-5-(4-(trifluoromethyl)pyrimidin-2-yl)-2,5- n/d Xdiazabicyclo[2.2.1]heptan-2-yl)benzamide n/d = Not Determined

TABLE 10 HDAC Inhibition (IC₅₀ μM) WC HDAC mouse cortical Compound NameEnzyme neurons(Z)-4-((5H-dibenzo[b,f]azepin-5-yl)methyl)-N-hydroxybenzamide A Y

C n/d (Z)-4-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxybutanamide D Y(E)-N-hydroxy-3-((Z)-2-oxo-5-phenyl-2,3-dihydro-1H- B Xbenzo[e][1,4]diazepin-8-yl)acrylamide(E)-N-hydroxy-3-((Z)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H- C Xbenzo[e][1,4]diazepin-8-yl)acrylamide(Z)-6-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxyhexanamide A X(Z)-N-hydroxy-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H- C Ybenzo[e][1,4]diazepin-8-yl)propanamide(Z)-N-hydroxy-6-(2-oxo-5-phenyl-2,3-dihydro-1H- C Xbenzo[e][1,4]diazepin-1-yl)hexanamide(Z)-N-hydroxy-8-(2-oxo-5-phenyl-2,3-dihydro-1H- C Xbenzo[e][1,4]diazepin-1-yl)octanamide

D n/d (Z)-2-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxyacetamide D n/d

C X

C X

C Y

C Y

A Y

C Y (E)-3-((Z)-5-(cyclopropylmethyl)-5H-dibenzo[b,f]azepin-2-yl)-N- C Yhydroxyacrylamide4-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin- D n/d6(11H)-yl)-N-hydroxybutanamide6-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin- C X6(11H)-yl)-N-hydroxyhexanamide7-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin- B X6(11H)-yl)-N-hydroxyheptanamide4-((11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3- C Ye][1,4]diazepin-6(11H)-yl)methyl)-N-hydroxybenzamide8-(11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3-e][1,4]diazepin- C W6(11H)-yl)-N-hydroxyoctanamide(E)-N-hydroxy-3-(4-(((Z)-2-oxo-5-phenyl-2,3-dihydro-1H- B Xbenzo[e][1,4]diazepin-1-yl)methyl)phenyl)acrylamide(E)-3-(4-(((Z)-5H-dibenzo[b,f]azepin-5-yl)methyl)phenyl)-N- B Xhydroxyacrylamide

B Y (E)-3-(4-((11-cyclopropyl-5-oxo-5H-benzo[b]pyrido[2,3- A We][1,4]diazepin-6(11H)-yl)methyl)phenyl)-N-hydroxyacrylamide(Z)-2-(4-((5H-dibenzo[b,f]azepin-5-yl)methyl)phenyl)-N- C Yhydroxyacetamide

C Y

A n/d 6-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N- A Xhydroxyhexanamide(Z)-5-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxypentanamide C Y(Z)-7-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxyheptanamide A X

C Y

C Y N-hydroxy-7-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Wyl)heptanamide7-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-N-hydroxyheptanamide C Z2-(benzhydrylamino)-N-hydroxypyrimidine-5-carboxamide A W2-(diphenylmethyleneaminooxy)-N-hydroxypyrimidine-5- D Y carboxamideN-hydroxy-6-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A W yl)hexanamideN-hydroxy-8-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- B X yl)octanamide2-(9H-fluoren-9-ylamino)-N-hydroxypyrimidine-5-carboxamide C Y

C Y N-hydroxy-N-(6-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A n/dyl)hexyl)formamide

A Y 2-(dipyridin-2-ylmethylamino)-N-hydroxypyrimidine-5- — W carboxamide8-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-N-hydroxy-8- C X oxooctanamideN-hydroxy-7-(11-oxodibenzo[b,f][1,4]thiazepin-10(11H)- A Wyl)heptanamide

A X N-hydroxy-4((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Wyl)methyl)benzamide

A W 2-(bis(4-fluorophenyl)methylamino)-N-hydroxypyrimidine-5- A n/dcarboxamide N-hydroxy-4-((6-oxophenanthridin-5(6H)-yl)methyl)benzamide AW N-hydroxy-4-(2-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Wyl)ethyloxodibenzo[b,f][1,4]oxazepin-10(11H)- yl)ethoxy)benzamideN-hydroxy-7-(phenanthridin-6-yloxy)heptanamide A YN-hydroxy-7-(6-oxophenanthridin-5(6H)-yl)heptanamide A WN-hydroxy-2-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- C Xyl)methyl)phenyl)acetamide6-(5-cyclopropyl-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)- C Xyl)-N-hydroxyhexanamide7-(5-cyclopropyl-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)- C Xyl)-N-hydroxyheptanamide

C X (E)-N-hydroxy-3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Xyl)methyl)phenyl)acrylamideN-hydroxy-3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- C Xyl)methyl)phenyl)propanamideN-hydroxy-4-((6-oxo-11,12-dihydrodibenzo[b,f]azocin-5(6H)- C Xyl)methyl)benzamide4-(2-(7-chloro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Xyl)ethylchloro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)-N-hydroxybenzamide2-(bis(4-fluorophenyl)methoxy)-N-hydroxypyrimidine-5- C Z carboxamide

C X (Z)-8-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxy-8-oxooctanamide C Y(Z)-7-(5H-dibenzo[b,f]azepin-5-yl)-N-hydroxy-7-oxoheptanamide A W

C X

A W N-hydroxy-4-(2-(5-oxobenzo[b]pyrido[3,2-f][1,4]oxazepin- A W6(5H)-yl)ethyloxobenzo[b]pyrido[3,2-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide(E)-N-hydroxy-4-(3-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- B Wyl)prop-1-enyl)benzamideN-hydroxy-4-(3-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- B Wyl)propyl)benzamideN-hydroxy-4-(3-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Xyl)prop-1-ynyl)benzamide4-(2-(2-fluoro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- A Wyl)ethylfluoro-11-oxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)-N-hydroxybenzamideN-hydroxy-4-(2-(5-oxo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)- A Xyl)ethyloxo-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)- yl)ethoxy)benzamideN-hydroxy-4-(2-(4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)- A Wyl)ethyloxo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)- yl)ethoxy)benzamideN-hydroxy-4-(2-(5-oxobenzo[b]pyrido[4,3-f][1,4]oxazepin- A W6(5H)-yl)ethyloxobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamideN-hydroxy-3-(4-((11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- C Xyl)methyl)-1H-1,2,3-triazol-1-yl)propanamideN-hydroxy-4-(2-(2-methyl-5-oxo-1,2,3,4- A Wtetrahydrobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethylmethyl-5-oxo-1,2,3,4-tetrahydrobenzo[b]pyrido[4,3-f][1,4]oxazepin-6(5H)-yl)ethoxy)benzamide4-(2-(dibenzo[b,f][1,4]oxazepin-10(11H)-yl)-2- C Xoxoethyldibenzo[b,f][1,4]oxazepin-10(11H)-yl)-2-oxoethoxy)-N-hydroxybenzamide

A W

C Z 2-fluoro-N-hydroxy-4-(2-(11-oxodibenzo[b,f][1,4]oxazepin- B n/d10(11H)-yl)ethyloxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzamideN-hydroxy-3-(2-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- C Zyl)ethyloxodibenzo[b,f][1,4]oxazepin-10(11H)- yl)ethoxy)benzamide3-fluoro-N-hydroxy-4-(2-(11-oxodibenzo[b,f][1,4]oxazepin- B W10(11H)-yl)ethyloxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzamide

C n/d N-hydroxy-4-(11-oxodibenzo[b,f][1,4]oxazepin-10(11H)- C Zyl)benzamide(Z)-3-((5H-dibenzo[b,f]azepin-5-yl)methyl)-N-hydroxybenzamide C n/dbenzyl 4-(5-(hydroxycarbamoyl)pyrimidin-2-yl)-1,4-diazepane-1- B Xcarboxylate

C n/d 4-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-N- A n/dhydroxybenzamide2-(4-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,4-diazepan-1- A Yyl)-N-hydroxypyrimidine-5-carboxamide

C n/d (S)-2-(2-(1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-N- C n/dhydroxypyrimidine-5-carboxamide2-chloro-N-hydroxy-4-(2-(11-oxodibenzo[b,f][1,4]oxazepin- D n/d10(11H)-yl)ethyloxodibenzo[b,f][1,4]oxazepin-10(11H)-yl)ethoxy)benzamide (Z)-N-hydroxy-4-(1-methyl-2-oxo-2,3-dihydro-1H- C Ybenzo[e][1,4]diazepin-5-yl)benzamide3-((10H-phenothiazin-10-yl)methyl)-N-hydroxybenzamide C n/d4-(dibenzo[b,f][1,4]oxazepin-10(11H)-ylmethyl)-N- A n/d hydroxybenzamide4-((benzhydrylamino)methyl)-N-hydroxybenzamide A n/d

C n/d N-hydroxy-2-(3-phenyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- AX 7(8H)-yl)pyrimidine-5-carboxamide4-((6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indol-5-yl)methyl)- C n/dN-hydroxybenzamideN-hydroxy-2-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3- B Xa]pyrazin-7(8H)-yl)pyrimidine-5-carboxamideN-hydroxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole- D n/d8-carboxamide N-hydroxy-9H-pyrido[3,4-b]indole-3-carboxamide D n/d4-((6,11-dihydrodibenzo[b,e]oxepin-11-ylamino)methyl)-N- C n/dhydroxybenzamide2-((1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-3- C n/dyl)-N-hydroxypyrimidine-5-carboxamide2-((1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-3- C n/dyl)-N-hydroxypyrimidine-5-carboxamideN-hydroxy-2-((1R,5S)-1-phenyl-3-azabicyclo[3.1.0]hexan-3- C n/dyl)pyrimidine-5-carboxamideN-hydroxy-4-((2-phenyl-1H-indol-1-yl)methyl)benzamide C n/d3-((10H-phenoxazin-10-yl)methyl)-N-hydroxybenzamide D n/d(Z)-4-(7-bromo-2-oxo-2,3-dihydro-1H-thieno[2,3-e][1,4]diazepin- C n/d5-yl)-N-hydroxybenzamide 4-((diphenylamino)methyl)-N-hydroxybenzamide Cn/d 3-((diphenylamino)methyl)-N-hydroxybenzamide D n/d(Z)-N-(5H-dibenzo[b,f]azepin-5-yl)methyl)benzyl)-N- C n/dhydroxyformamide N-hydroxy-2-((1R,5S)-1-(3-(trifluoromethyl)phenyl)-3- Cn/d azabicyclo[3.1.0]hexan-3-yl)pyrimidine-5-carboxamideN-hydroxy-2-((1R,5S)-1-(4-(trifluoromethyl)phenyl)-3- C n/dazabicyclo[3.1.0]hexan-3-yl)pyrimidine-5-carboxamide n/d = NotDetermined

Assay Example 4 In Vivo Drosophila Fly Assay for Treatment ofHuntington's Disease

The present invention discloses methods and pharmaceutical compositionsfor treating polyglutamine (polyQ) expansion diseases. In certainpreferred embodiments, the disease is selected from the group consistingof Huntington's Disease (HD), Dentatorubralpallidoluysian atrophy(DRPLA), spinal and bulbar muscular atrophy (SBMA), and fivespinocerebellar ataxias (SCA1, SCA2, SCA3/MJD (Machado-Joseph Disease),SCA6 and SCA7).

The suitability of a compound for treatment of a polyglutamine (polyQ)expansion diseases can be assessed in any of a number of animal models.For example, mice transgenic for an expanded polyglutamine repeat mutantof ataxin-1 develop ataxia typical of spinocerebellar ataxia type 1(SCA-I) are known (Burright et al., 1995, Cell 82: 937-948; Lorenzettiet al., 2000, Hum. MoI. Genet. 9: 779-785; Watase, 2002, Neuron 34:905-919), and can be used to determine the efficacy of a given compoundin the treatment or prevention of neurodegenerative disease. Additionalanimal models, for example, for Huntington's disease (see, e.g.,Mangiarini et al., 1996, Cell 87: 493-506, Lin et al., 2001, Hum. MoI.Genet. 10: 137-144), can be used to evaluate the efficacy of thecompounds of the present invention in a similar manner.

Animal models are not limited to mammalian models. For example,Drosophila strains provide accepted models for a number ofneurodegenerative disorders.

The Drosophila Huntington's Disease assay used to screen compounds ofthe present invention followed that of WO 2007/002497, which is herebyincorporated by reference in its entirety.

Drosophila melanogaster Fly Production:

Briefly, parental (model and driver) lines are maintained in sufficientquantities to provide virgins and males for assay crosses as well asperpetuating the lines. Disease model flies are maintained with thedisease genes “silent”, functionally linked to a UAS enhancer element.The “driver” lines contain a GAL4 element under the control of atissue-specific promoter. These are crossed together to generate theassay flies which have tissue-specific (i.e. CNS) expression of thedisease gene(s).

Weekly assay crosses are set up with sufficient virgins and males togenerate enough assay embryos for sorting. Approximately 50,000 malesand 75,000 virgins are crossed in population cages. Embryos arecollected for an eight hour window two days later. The embryos are thensorted onto 16 mm assay vials containing regular fly media and allowedto develop. Flies containing both the GAL4 driver element and thedisease gene(s) are detected by the presence of GFP, a fluorescingprotein. Approximately 10 assay flies eclose per vial, the optimalnumber for the behavioral assay. Once the flies eclose, they aretransferred onto assay vials containing liquid Drosophila food.Similarly, control crosses are set up with virgins of the driver andmales from a non-disease UAS line. Throughout fly production and theassay days, all flies are maintained at constant temperature andhumidity, with preset light cycle, optimized for the particular linesand crosses.

Quality control (QC) for the parental lines is carried out weekly bycollecting a sample of random male flies from each line. Single-fly PCRis carried out to ascertain the presence of the GAL4 or UAS element. Ifgreater than 5% of the individuals lack the appropriate element, theassay cross is aborted. A second form of QC is also carried out toensure that the GAL4 element is able to drive expression of a transgene.A sample of individual “driver” virgins is crossed to UAS-GFP males.Their progeny are visually checked for GFP expression in the appropriatetissues. Lack of GFP in greater than 4% of the crosses results in theassay being aborted.

Compound Handling and Dosing:

Test compounds are weighed out and dissolved in DMSO at stockconcentrations 100× what is desired in the assay and arrayed into96-well master plates, including wells for DMSO-only controls and thepositive control(s). A single well is reserved for a colored dye used toensure proper orientation of compounds during drug dispensing and flytransfer. Replicate daughter plates for each day of the assay arestamped out. The plates are bar coded and stored at −20 C until used forthe assay.

For a particular assay day, the plates are thawed and a robotic liquidhandler is used to dilute the test compound into the liquid fly food anddispense the mixture into the assay vials. For Huntington Disease (HD)models, eight replicates per single treatment (one compound, oneconcentration) are dispensed. Fresh test compound treated media is madedaily during an assay.

Automated Behavioral Assay:

On the day the assay flies eclose (emerge from larvae; assay Day 0) theyare transferred to the test compound treated vials. On assay Day 1, theflies are transferred onto clean test compound treated vials one hourbefore assay time. They are then placed in the assay machine toacclimate to the appropriate climate conditions.

The assay machine is an environmentally-enclosed and controlled robotthat can maintain user-set temperature and humidity. The machine canhold up to sixteen 96-vial racks in four quadrants, for a total of 1536vials. There are four camera stations, which hold four vials each and aCCD camera for movie capture. A robotic arm carries a gripper whichpicks up four vials at a time, places them in a designated camerastation, taps the vials to stimulate fly climbing behavior, then movesonto the next rack to pick up four vials into the next camera station,etc. For HD assays, each vial is recorded four times for 7.5 seconds,the recording starting after the vials are tapped.

After the assay run, the racks of flies are returned to the warm roomsat the designated temperature and humidity. This process is repeated forall days of the assay (10 for HD assays).

The movies are then “tracked”; using a number of parameters given in theTrackingServer custom application, movement of the flies in each movieis converted into a tracking file. Each tracking file is then processedby the scoring server, converting the movement of the flies into anumber of measurements for each movie for each individual vial for aparticular trial day. The measurements for each movie are outputted as a.CSV file.

Analysis and Hit Determination:

Examples of metrics are included below:

-   -   (1) xpos: The average of all the x-positions of all detected        regions (i.e. flies) before 7.5 seconds in the tracking file.    -   (2) xspeed: The average of all the x-speeds of all detected        regions before 7.5 seconds in the tracking file.    -   (3) speed: The average of all the speeds of all detected regions        before 7.5 seconds in the tracking file.    -   (4) turning: The average of all turning angles of all detected        regions before 7.5 seconds. The turning is determined by the        angle between a speed vector and the previous one.    -   (5) stumbling: The average of all stumbling angles of all        detected regions before 7.5 seconds. The stumbling is determined        by the angle between a speed vector and the orientation of the        corresponding region.    -   (6) size: The average area of all detected regions.    -   (7) tcount: The total number of trajectories.    -   (8) pcount: The total number of detected regions.    -   (9) tlength: The total sum of all trajectory lengths.    -   (10) crosshigh: The number of trajectories that cross or start        above a certain high threshold    -   (11) crosslow: The number of trajectories that cross or start        above a certain high threshold    -   (12) fcount: The maximum number of detected regions in any one        frame. Used as an estimate of the number of flies in the video.

The particular spectrum of metrics to detect improvement in behavior ofa treated disease fly vs. an untreated disease fly differs from diseasemodel to disease model. Metrics are chosen based on the dynamic range ofi) the difference between untreated disease and positive control and ii)the difference between untreated disease and non-disease. For theHuntington's disease screening model, speed is the best metric. Summarymetrics for performance are used to determine effect sizes of treatmentsvs. control. The summary metrics used for the HD model are “earlyspeed”, the average speed for days 1-7 and “late speed”, the averagespeed for days 8-10. These day ranges were chosen based on the shape ofthe speed curves and the t-statistic for all different day ranges.Toxicity for a compound treatment is determined by fly loss throughoutthe assay.

The effect sizes for the performance metrics are calculated for thedifferent treatments by dividing the value for the metric by the pooledstandard deviation for the assay. Certain systematic variations in thedata can be modeled and integrated into the analysis. For example, alinear statistical model for rack position or drug dispense order can beapplied to correct the effect sizes. A final assessment of assay anddata quality is done by the experimenters.

For test compound treatments, a multiple repeat strategy is used todefine compound hits. Statistical power is set to decrease the number offalse positives and to increase the number of true positives. Athreshold of effect size is set for each of three assays per treatment.A treatment below threshold for the first or second pass is not run in athird pass without convincing rationale. For current screening with theHD model, the effect size threshold for a hit after three passes is >0.4early speed (effect size) or >0.6 late speed (effect size). Strong hitsare defined are effect sizes of >0.8 early speed and >1.2 late speed.Effect size is defined as the difference between DMSO-carrier controland test compound divided by the pooled standard deviation in the wholeassay (preferred test compounds have early effect size >0.4 or lateeffect size >0.6; more preferred test compounds have early effectsize >0.6 or late effect size >1.2). TSA was used as a HDAC positivecontrol.

Speed 1 to 7 (concentration) Speed 8 to 10 (concentration) 30 100 150200 300 30 100 150 200 300 STRUCTURE uM uM uM uM uM uM uM uM uM uM

0.02 0.48 0.506 −0.14 0.3 −0.112

0.118 −0.004 0.444 −0.108 0.139 0.47

0.05 −0.01 0.68 0.15 0.16 0.35

0.28 0.64 0.66 0.22 0.46 0.58

0.63 0.38 0.03 0.28 0.02 −0.29

0.468 0.82 0.3 0.087 0.82 0.54

0.781 0.549 0.411 0.291 0.376 0.471

0.84 0.68 0.26 0.5

−0.007 0.046 0.829 −0.134 −0.369 −0.107

0.495 0.33 −0.469 0.338 0.368 0.512

0.493 0.588 0.412 0.036 0.359 0.439

Compounds according to the present invention are able to cross the bloodbrain barrier in treated mice and inhibit a histone deacetylase in acell thereacross, thereby increasing histone acetylation in the brain.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

1. A compound represented by Formula (I):

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, and racemic mixtures, diastereomers andenantiomers thereof, wherein Z is selected from the group consisting of—N(R¹)OR² and H; L is selected from the group consisting of a covalentbond and —N(OR²)—; wherein, when L is —N(OR²)—, Z is H; and wherein,when Z is H, L is —N(OR²)—; J is selected from the group consisting of acovalent bond, ═CH—, —C₁-C₈alkyl-,—C₀-C₃alkyl-C₁-C₈heteroalkyl-C₀-C₃alkyl-,—C₀-C₃alkyl-C₂-C₈alkenyl-C₀-C₃alkyl-,—C₀-C₃alkyl-C₂-C₈alkynyl-C₀-C₃alkyl-, —C₀-C₆alkyl-aryl-C₀-C₆alkyl-,—C₀-C₆alkyl-aryl-C₂-C₆heteroalkyl-,—C₀-C₃alkyl-C₁-C₆heteroalkyl-aryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₁-C₆heteroalkyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkyl-cycloalkyl-C₀-C₆alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₆alkyl-,—C₄-C₆heterocyclyl-aryl-C₀-C₆alkyl-,—C₄-C₆heterocyclyl-aryl-C₀-C₆heteroalkyl-,—C₀-C₆alkyl-C₄-C₆heterocyclyl-C₀-C₆alkyl-,—C₀-C₆alkyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkylheteroaryl-C₀-C₆heteroalkyl-,—C₄-C₆heterocyclyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkynyl-, —C₀-C₆alkyl-heteroaryl-C₂-C₆alkynyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkynyl-C₂-C₆alkenyl-,—C₀-C₆alkyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-heteroaryl-C₂-C₆alkenyl-,—C₀-C₃alkyl-C₂-C₆alkenyl-aryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkenyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkynyl-aryl-C₀-C₆alkyl-,—C₀-C₃alkyl-C₂-C₆alkynyl-heteroaryl-C₀-C₆alkyl-,—C₀-C₆alkylaryl-aryl-C₀-C₆alkyl-,—C₀-C₆alkylaryl-heteroaryl-C₀-C₆alkyl-,—C₀-C₃alkyl-heteroaryl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heteroaryl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-aryl-C₀-C₃alkyl-, and—C₀-C₆alkyl-C₃-C₆cycloalkyl-C₀-C₆alkyl-, wherein each alkyl, alkenyl,alkynyl, heteroalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkylmoiety is optionally substituted, and wherein when J is ═CH—, Q is acovalent bond and B is attached through a carbon sp² to J; Q is selectedfrom the group consisting of an optionally substituted:

or where possible, an (R,R) or (S,S) enantiomer or a mixture ofenantiomers thereof, wherein G and G¹ are independently selected fromcarbon and N; the variables l, m, n, o and p denote numbers that areeach independently selected from 0, 1, 2 or 3 provided that the sumtotal of l, m, n, o and p is 4, 5, 6 or 7, such that the grouprepresented by Q comprises a 6, 7, 8 or 9 membered bridged or fusedheterocyclyl, respectively, and further provided that when G and G¹ areboth N then the sum total of l and o is not zero, and the sum total of mand p is not zero, and wherein n is an integer ranging from 0 to 3; U isselected from the group consisting of —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-,—C₁-C₈alkyl-, —C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,—C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond and—O—C₂-C₄alkyl-; and U¹ is selected from the group consisting of H,—C(R¹)(R²)—, —C₀-C₈alkyl-C(O)—C₀-C₃alkyl-, —C₁-C₈alkyl-,—C₀-C₈alkyl-N(R³)—C(O)—C₀-C₃alkyl-, —C(R¹)(R²)—N(R³)—C(O)—C₀-C₃alkyl-,—C(R¹)(R²)—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-O—C(O)—C₀-C₃alkyl-,—C(R¹)(R²)—O—C(O)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—C(S)—C₀-C₃alkyl-,—C₀-C₈alkyl-O—C(S)—C₀-C₃alkyl-, —C₀-C₈alkyl-N(R³)—S(O)₂—C₀-C₃alkyl-,—C₀-C₈alkyl-heterocyclyl-C₀-C₃alkyl-, a covalent bond,(R³)(R^(3a))N—C₂-C₄alkyl-, —O—C₂-C₄alkyl-, and R³—O—C₂-C₄alkyl-; or Q isselected from the group consisting of a covalent bond, —C₁-C₈alkyl-,—C₁-C₈alkyl-, —C₁-C₈heterocyclyl-, ═N—O—, —C₀-C₆alkyl-N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-O—C₀-C₃alkyl-, —C₀-C₆alkyl-S(O)₀₋₂—C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C₀-C₆alkyl-C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-O—C₀-C₃alkyl-, —C₀-C₆alkyl-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)₀₋₂—N(R³)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—N(R³)-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-O—C(O)—O-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—O-cycloalkyl-C₀-C₃alkyl-,—C₀-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-, —C₀-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₄alkyl-,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C₀-C₆alkyl-SO₂—N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—SO₂—C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₀-C₆alkyl-S—C₀-C₃alkyl-,—C₀-C₆alkyl-S(O)—C₀-C₃alkyl-, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl-,—C₀-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl-, ═N—O—C₀-C₃alkyl-,-heterocyclyl-C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C(O)—C₀-C₆alkyl-bridgedheterocyclyl-C₀-C₃alkyl-,—N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-SO₂—N(R³)—, —C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl moiety is optionally substituted; wherein

is selected from the group consisting of b-1a to b-1k and b-1 to b-125,and wherein when Q is attached to

via ═N—O—, or ═N—O—C₀₋₃alkyl, it is attached through carbon Sola-Pennaet al.² in

and wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl andalkenyl moiety is optionally substituted; and wherein when Q is acovalent bond and J is attached to

via ═CH—, then it is attached through carbon sp² in

or when

is selected from the group consisting of b-1 to b-121 and is attached toQ via a N in

then Q is selected from the group consisting of a covalent bond,—C(O)—C₁-C₃alkyl-O—, —C₁-C₈alkyl-, —C₂-C₆alkyl-N(R³)—C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-, —C₀-C₆alkyl-C(O)—C₀-C₃alkyl-,—C₀-C₆alkyl-O—C₀-C₃alkyl-, —C₁-C₆alkyl-(CR³═CR³)₁₋₂—C₀-C₆alkyl-,—C₁-C₆alkyl-(C≡C)₁₋₂—C₀-C₆alkyl-, —C₂-C₆alkyl-N(R³)—C(O)—C₀-C₃alkyl,—C₂-C₆alkyl-N(R³)—C(O)-alkenyl-C₀-C₃alkyl,—C₀-C₆alkyl-C(O)—N(R³)—C₀-C₄alkyl-, —C(O)—O—C₀-C₄alkyl,—C₀-C₆alkyl-S(O)₂—N(R³)—C₀-C₃alkyl, —C₂-C₆alkyl-N(R³)—S(O)₂—C₀-C₃alkyl,—C₂-C₃alkyl-N(R³)—S(O)₂—N(R³)—C₀-C₃alkyl-, —C₂-C₆alkyl-S-C₀-C₃alkyl,—C₂-C₆alkyl-S(O)—C₀-C₃alkyl, —C₀-C₆alkyl-S(O)₂—C₀-C₃alkyl,—C₂-C₆alkyl-N(R³)—C(O)—N(R³)—C₀-C₃alkyl, —C₂-C₃alkyl-C═N—O—C₀-C₃alkyl,—SO₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-N(R³)—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C(O)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-N(R³)—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C(S)—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₂-C₄alkyl-N(R³)—S(O)₂—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-S(O₂)—N(R³)—,—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—N(R³)— and—C₀-C₆alkyl-heterocyclyl-C₀-C₃alkyl-C(O)—O—, wherein each alkyl,heterocyclyl and alkenyl moiety is optionally substituted, and whereinthe heterocyclyl moiety is optionally bridged with —(CH₂)₀₋₃—; R¹ and R²are independently selected from the group consisting of —H, C₁-C₆alkyl,aryl, heteroaryl, heterocyclyl, cycloalkyl and a protecting group; eachR³ is independently selected from the group consisting of —H, alkyl,C₀-C₃alkyl-heterocyclyl, C₁-C₃alkyl-C₂-C₆alkenyl,C₁-C₃alkyl-C₂-C₃alkynyl, —C₂-C₄alkyl-OR¹, —C₂-C₄alkyl-NR^(3b)R^(3c),—C₂-C₄alkyl-NR¹R², heteroalkyl, C₀-C₆alkylheteroaryl, C(O)CF₃,—C(O)—NH₂, —C(O)—NR^(3b)R^(3c), —C(O)—NR¹R², —C(O)—OR¹, —S(O)₂—NR¹R²,—S(O)₂—R¹, —C(O)—R¹, —C₃-C₆cycloalkyl, —C₀-C₃alkyl-C₃-C₇cycloalkyl,—C₁-C₆alkylaryl, aryl, C₀-C₃alkyl-heteroaryl and heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl,aryl and heteroaryl moiety is optionally substituted with from one tothree independently selected substituents; each R^(3a) is independentlyselected from the group consisting of —H, alkyl, heterocyclyl,C₂-C₆alkenyl, C₂-C₃alkynyl, C₂-C₄alkyl-OR¹, heteroalkyl, heteroaryl,C₀-C₆alkylheteroaryl, C(O)CF₃, —C(O)—NH₂, —C₃-C₆cycloalkyl,-alkyl-C₃-C₆cycloalkyl, —C₁-C₆alkylaryl, aryl, alkylheteroaryl andheteroaryl, covalent bond, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moiety isoptionally substituted; wherein R³ and R^(3a), together with the atom towhich they are attached, optionally form a heterocyclic ring, whereinthe heterocyclyl moiety is optionally substituted; wherein R^(3b) andR^(3c), together with the atom to which they are attached, optionallyform a heterocyclic ring, wherein the heterocyclyl moiety is optionallysubstituted; provided that

is absent when Q is structure (a-1), (a-2), (a-3), (a-20) or when U¹ isH, N(R³)(R^(3a))—C₂-C₄alkyl- or R³—O—C₂-C₄alkyl-;

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, heterocyclyl, cycloalkyl,heterocyclyl-alkyl, cycloalkyl-alkyl, C₁-C₁₀alkyl,(aryl)₂-CH—C₀-C₆alkyl-, (aryl)(heteroaryl)CH—C₀-C₆alkyl- and(heteroaryl)₂CH—C₀-C₆alkyl-, each of which is optionally substituted; or

is a radical selected from the group consisting of

wherein

are independently selected from phenyl, a 5- or 6-membered heteroaryland a heterocyclyl, wherein each of which is optionally substituted withone to three independently selected substituents; provided that when

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, heterocyclyl, cycloalkyl,heterocyclyl-alkyl, cycloalkyl-alkyl, C₁-C₁₀alkyl,(aryl)₂-CH—C₀-C₆alkyl-, (aryl)(heteroaryl)CH—C₀-C₆alkyl- and(heteroaryl)₂CH—C₀-C₆alkyl-, each of which is optionally substituted,then Q is selected from the group consisting of a-3, a-4, a-5, a-6, a-7,a-8, a-9, a-10, a-11, a-12, a-13 and a-14, wherein each A isindependently selected from the group consisting of N, —N-oxide, —CH═and —C(R⁴)═, wherein no more than two A per 5 or 6 membered ring are Nin a

group, and wherein no more than one A is —N-oxide; the group M¹-M² isselected from the group consisting of a covalent bond, —N(R³)CH₂—,—CH₂N(R³)—, —S(O)₀₋₂—CH₂—, —CH₂S(O)₀₋₂—, —O—CH₂—, —CH₂—O—, —C(O)N(R³)—,—C(O)—O—, —C(O)—CH₂—, —CH(OH)—CH₂—, —CH(F)—CH₂—, —CH₂—C(O)—,—CH₂—CH(OH)—, —CH₂—CH(F)—, —N(R³)—C(O)—, —SO₂N(R³)—, —N(R³)SO₂—,—CH(R⁴)CH₂—, —CH₂CH(R⁴)—, —N═C(R⁴)—, —C(R⁴)═N—, —CH₂—CH₂—, —CH═CH—,—CH(R³)—CH(R³)—, —C(R³)═C(R³)—, —C(R⁴)═C(R⁴)—, —CF═CH—, —CH═CF—,

—CH₂—, —C(R³)(R^(3a))—, —S(O)₀₋₂—, —N(R³)—, or absent; M³ is selectedfrom the group consisting of

or M³ is

wherein Q is attached to

via ═N—O—, or ═N—O—C₀₋₃alkyl, or J is attached to

via ═CH—, wherein * represents the point of attachment to Q; M⁴ isselected from the group consisting of

and covalent bond; wherein, when M¹-M² is a covalent bond, M⁴ isselected from the group consisting of

the groups D¹-D² and D^(1a)-D^(2a) are selected from the groupconsisting of

wherein, * represents the point of attachment to Q; D³ is selected fromthe group consisting of a covalent bond,

wherein the

are optionally substituted; D⁴ is selected from the group consisting of

wherein the

is optionally substituted; the group E¹-E² is selected from the groupconsisting of

wherein * represents the point of attachment to Q; and E³ is selectedfrom the group consisting of —C(O)—, —C(S)—, —CH₂—, —C(OH)₂— and—C═N(R³)—; and R⁴ is independently selected from the group consisting of—H, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkyl-R³,—C₀-C₆alkyl-OR³, —C₀-C₆alkyl-OR¹, —C₀-C₆alkyl-C(O)—OR³,—C₀-C₆alkyl-C(O)NR³R^(3a), —CH═CH—C(O)—OR³, —CH═CH—C(O)—N(R³)(R^(3a)),—N(R³)—C(O)—CF³, —N(R³)—C₂-C₆alkyl-N(R³)(R^(3a)),—C₀-C₆alkyl-N(R³)(R^(3a)), —N(R³)—C(O)—C₁-C₆alkyl-R³,—N(R³)—S(O)₂—C₁-C₆alkyl-R³, —S(O)₂—N(R³)R^(3a),—O—C₂-C₆alkyl-N(R³)(R^(3a)), —O—C₂-C₆alkyl-OR¹, —S—R³,—S(O)—C₁-C₆alkyl-R³, —S(O)₂—C₁-C₆alkyl-R³, C₃-C₆cycloalkyl,heterocyclyl, C₄-C₇heterocyclyl-R³, —O—C₂-C₄alkyl-heterocyclyl,—O-heterocyclyl-C(O)—OR³, —O—C₀-C₄alkyl-aryl, —O—C₀-C₄alkyl-heteroaryl,—O—C(O)—NR³—C₀-C₄alkyl-aryl, —O—C(O)—NR³—C₀-C₄alkyl-heteroaryl,—O—C₀-C₄alkyl-heterocyclylaryl, —O—C₀-C₄alkyl-heterocyclyl-heteroaryl,—N(R³)—C₂-C₄alkyl-heterocyclyl,—N(R³)C(O)N(R³)—C₀-C₄alkyl-heterocyclyl-R³, —C₀-C₄alkyl-OC(O)—R³,—C₀-C₄alkyl-N(R³)C(O)—O—R³, —C₀-C₄alkyl-heterocyclyl-C(O)—O—R³,—N(R³)—C₂-C₄alkyl-heterocyclyl, F, Cl, Br, I, NO₂, —CF₃, —OCF₃, —OCHF₂,—SCF₃, —SF₅, —SO₃H, —CN, —C₁-C₆ alkylaryl, aryl, heteroaryl, cycloalkyl,—C₁-C₆ alkylheteroaryl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl and heteroaryl moeity of theaformentioned R⁴ is optionally substituted; or

is selected from the group consisting of structures b-1a to b-1k and(b-1) to (b-125) and Q-J-L taken together is selected from the groupconsisting of —C₃-C₈alkyl-, —C(O)—C₃-C₈alkyl-,—C₀-C₃alkyl-O—C₃-C₈alkyl-, —C₀-C₃alkyl-C₁-C₄alkenyl-C₀-C₃alkyl-,═N—O—C₁-C₈alkyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkenyl-, ═N—O—C₀-C₃alkyl-aryl-C₀-C₃alkynyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkenyl-,═N—O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkynyl-, —C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-aryl-C₂-C₄alkenyl-, —C₀-C₃alkyl-aryl-C₂-C₄alkynyl-,—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heteroaryl-C₁-C₃alkenyl-,—C₀-C₃alkyl-heteroaryl-C₁-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-aryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)—N(R³)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)—C₀-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₀-C₃alkyl-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₀-C₃alkyl-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-N(R³)—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₀-C₃alkyl-O—C(O)-heterocyclyl-C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₀-C₃alkyl-,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkenyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-aryl-C₂-C₄alkynyl,—C₂-C₄alkyl-O—C₀-C₃alkyl-heteroaryl-C₀-C₃alkyl,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkenyl-,—C₂-C₄alkyl-O—C₁-C₃alkyl-heteroaryl-C₂-C₃alkynyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U-bridgedheterocyclyl-N(R³)-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-U—N(R³)-bridgedheterocyclyl-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-heteroaryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-aryl-C₀-C₆alkyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-aryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-bridgedheterocyclyl-U-heteroaryl-C₂-C₆alkenyl-, —C₀-C₆alkyl-N(R³)-bridgedheterocyclyl-U-heteroaryl-C₂-C₆alkenyl-, and —C₀-C₆alkyl-bridgedheterocyclyl-N(R³)—U-heteroaryl-C₂-C₆alkenyl-, wherein each alkyl,alkenyl, aryl, alkynyl, heteroaryl and heterocyclyl moiety is optionallysubstituted; and wherein the bridge is methylene or propylene; providedthat Formula (I) excludes those compounds wherein -Q-J-L-C(O)Z isoptionally substituted—C₁-C₁₃alkyl-N(R³)—C₀-C₆alkyl-aryl-C₂alkenyl-C(O)NHOH; and

is selected from the group consisting of aromatic polycycles,non-aromatic polycycles, mixed aryl and non-arylpolycycles,polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl andnon-aryl polyheterocycles, each of which is optionally substituted; andprovided that Formula (I) excludes compounds of Formula (A)

wherein R⁹⁰⁶ is selected from the group consisting of aryl andheteroaryl; T⁹⁰⁶ is selected from the group consisting of—C₀₋₆alkyl-S(O)₂—C₀₋₆alkyl-, —C₀₋₆alkyl-C(O)—C₀₋₆alkyl- and C₁₋₃alkyl,wherein T⁹⁰⁶ is substituted at the carbon atom attached to R⁹⁰⁶ with amoiety selected from the group consisting of aryl, heteroaryl,cycloalkyl and heterocycle; A⁹⁰⁶ is an optionally substituted unbridgedheterocycle; Q⁹⁰⁶ is a bond; Het is an optionally substituted 5-memberedaryl ring; L⁹⁰⁶ is a bond or —C₁₋₄alkyl-; and R^(906a) is—N(R^(906b))OH, wherein R^(906b) is selected from the group consistingof H, optionally substituted alkyl and optionally substituted aryl; andprovided that Formula (I) excludes those compounds wherein -Q-J-L-C(O)Zis optionally substituted—C₀-C₄alkyl-X—C₁-C₄alkyl-phenyl-C₂alkenyl-C(O)NHOH;

is a 5- or 6-membered aromatic heterocyclic group condensed with acarbon ring or other heterocyclic ring, which

is substituted with 1 to 4 substituents selected from phenyl, another 5-or 6-membered aromatic heterocyclic group and a heterocyclic group, saidheterocyclic group being optionally substituted with C₁₋₄alkyl, a benzylgroup or a pyridylmethyl group; and X is a moiety having a structureselected from the group consisting of —C(O)N(R^(A1))—,—O—C(O)—N(R^(A1))—, —SO₂—, —N(R^(A2))SO₂—, wherein R^(A1) and R^(A2) areindependently —H or optionally substituted C₁-C₄alkyl; and provided thatFormula (I) excludes compounds wherein B-Q- is

and -J-L- is

wherein R is directly attached or attached through a linker, and isselected from the group consisting of substituted or unsubstituted aryl,cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino,9-purine-6-amine, thiazoleamino group, hydroxyl, branched or unbranchedalkyl, alkenyl, alkyoxy, aryloxy, arylalkyloxy and pyridine group,wherein the linker is selected from the group consisting of an amidemoiety, —O—, —S—, —NH— and —CH₂—; and provided that Formula (I) excludescompounds of Formula (B)

wherein R^(B) is H or phenyl; A^(B) is a bi- or tricyclic residueoptionally partially or totally unsaturated, and which optionallycontains one or more heteroatoms selected from the group consisting ofN, S and O, and optionally substituted by hydroxy, alkanoyloxy, primary,secondary or tertiary amino, aminoC₁-C₄alkyl, mono- ordi(C₁-C₄)alkyl-aminoC₁-C₄alkyl, halogen, C₁-C₄alkyl andtri(C₁-C₄)alkylammoniumC₁-C₄alkyl;

is a chain of 1 to 5 carbon atoms optionally containing a double bond oran NR group, wherein R is H or C₁-C₄alkyl; X^(B) is absent, an oxygenatom or an NR group, wherein R is H or C₁-C₄alkyl; and B^(B) is aphenylene or cyclohexylene ring; and provided that Formula (I) excludescompounds of Formula (D)

wherein A^(D) is selected from the group consisting of a 4- to10-membered aromatic or non-aromatic heterocyclyl; X^(D) is C═O orS(O)₂; R^(D1) is H or C₁-C₆alkyl; R^(D2) is independently selected fromthe group consisting of oxo, (C═O)—NH₂, C₁-C₆alkyl-aryl andheterocyclyl, when A^(D) is a non-aromatic heterocycle, wherein saidalkyl, and aryl moieties are optionally substituted with one to threeR^(b); or R^(D2) is independently selected from the group consisting ofOH, NO₂, (C═O)₀₋₁—O₀₋₁—C₁-C₆alkyl, CN, (C═O)₀₋₁—O₀₋₁—C₃-C₁₀cycloakyl,halogen, (C═O)₀₋₁—N(R^(a))₂, CF₃, NH—S(O)₀₋₂—R^(a),(C═O)₀₋₁—O₀₋₁-heterocyclyl, (C═O)₀₋₁—O₀₋₁-aryl, S(O)₀₋₂—R^(a),NH(C═O)R^(a), C₁-C₆alkyl-aryl and heterocyclyl, when A^(D) is anaromatic heterocyclyl, wherein said alkyl, cycloalkyl, aryl andheterocyclyl are optionally substituted with one to three R^(b); R^(a)is independently H or C₁-C₆alkyl; and R^(b) is independently selectedfrom the group consisting of oxo, NO₂, N(R^(a))₂, OH, CN, halogen, CF₃and C₁-C₆alkyl; and provided that Formula (I) excludes compounds ofFormula (E)

wherein A^(E) is selected from the group consisting of —CH₂—O—, —CH₂—S—,—CH₂—CH₂— and —NH—CO—; X^(E) is selected from the group consisting of—N(R^(E3))—, ═C(O) and —CH(OH)—; Y^(E) is selected from the groupconsisting of O, S and —N(R^(E4))—; Z^(E) is selected from the groupconsisting of a straight chain C₄-C₈alkylene, wherein one CH₂ group maybe replaced by an oxygen or a sulfur atom, or wherein 2 carbon atomsform a C═C double bond, and which is either unsubstituted or substitutedby one or two substituents selected from C₁-C₄alkyl and halogen; R^(E1)and R^(E2) are independently selected from the group consisting of H,halogen, C₁-C₄alkyl, trifluoromethyl, hydroxy, C₁-C₄alkoxy, benzyloxy,C₁-C₃alkylenedioxy, nitro, amino, C₁-C₄alkylamino,di[(C₁-C₄)alkyl]-amino, and C₁-C₄alkanoylamino; and R^(E3) and R^(E4)are independently selected from H and C₁-C₄alkyl; and provided thatFormula (I) excludes compounds of Formula (F)A^(F)-Q^(1F)-J^(F)-Q^(2F)-C(O)—NH—OH  (F) wherein A^(F) is a C₅-C₂₀ arylgroup or a 5-20 membered heteroaryl group, each having one ring or twoor more fused rings, wherein at least one ring is aromatic, said ary andheteroaryl groups being optionally substituted; Q^(1F) is a linker grouphaving a backbone length of at least 2 carbon atoms, the linker beingoptionally substituted; J^(F) is —N(R^(F))—C(O)— or —C(O)—N(R^(F))—;Q^(2F) is selected from the group consisting of C₁-C₁₀alkyl, C₅-C₂₀aryl,5 to 20 membered heteroaryl, C₅-C₂₀aryl-C₁-C₁₀alkyl, 5 to 20 memberedheteroaryl-C₁-C₁₀alkyl, C₁-C₁₀alkyl-C₅-C₂₀aryl and C₁-C₁₀alkyl-5 to 20membered heteroaryl, each of which is optionally substituted; and R^(F)is selected from the group consisting of H, C₁-C₇alkyl,C₃-C₂₀heterocyclyl and C₅-C₂₀aryl, each of which is optionallysubstituted; and provided that Formula (I) excludes compounds wherein Zis —N(R¹)(OR²); R¹ and R² are independently selected from the groupconsisting of H, C₁-C₆alkyl, aryl and heteroaryl; L is a bond; and

is selected from the group consisting of hydrogen, aryl, aryl-alkyl-,heteroaryl, heteroaryl-alkyl-, heterocyclyl, cycloalkyl,heterocyclyl-alkyl, cycloalkyl-alkyl, C₁-C₁₀alkyl,(aryl)₂-CH—C₀-C₆alkyl-, (aryl)(heteroaryl)CH—C₀-C₆alkyl- and(heteroaryl)₂CH—C₀-C₆alkyl-, each of which is optionally substituted;and Q comprises a ring selected from the group consisting of

wherein Y^(F) is nitrogen or —CH<, and Z^(F) is oxygen, NH or —CH₂— ifZ^(F) is not bonded to

or Z^(F) is nitrogen or —CH< if Z^(F) is bonded to

or

is selected from the group consisting of b-53, b-62 (wherein D³ is

b-69 (wherein R⁴ is H), b-70, b-72 (wherein D³ is

b-92 and b-93; and Q-J is selected from the group consisting of—X^(F)—C₀₋₄alkyl-aryl-C₀₋₄alkyl-,—X^(F)—C₀₋₄alkyl-heteroaryl-C₀₋₄alkyl-, and—X^(F)—C₀₋₄alkyl-heterocyclyl-C₀₋₄alkyl-, wherein said alkyl, aryl,heteroaryl, and heterocyclyl are optionally substituted, and whereinsaid heterocyclyl is a mono- or bi-saturated or mono- or bi-unsaturatedheterocyclic ring, and wherein X^(F) is selected from the groupconsisting of

wherein the left side attaches to

and wherein r and s are each independently 0, 1, 2, 3, 4 or 5, wherein rand s cannot be both 0 and when r or s are 0 then a direct bound inintended; each r′ is independently 0, 1, 3, 3 or 4 and r′ cannot be 0when s is 0; R^(4A) is H, C₁₋₆alkyl or phenyl; Y^(F) is nitrogen or—CH<, and Z^(F) is oxygen, NH or —CH₂— if Z^(F) is not bonded to

or Z^(F) is nitrogen or —CH< if Z^(F) is bonded to

and provided that Formula (I) excludes those compounds having thefollowing structure:

wherein X⁹ is selected from the group consisting of CO, SO₂ and CH₂; Y⁹is selected from the group consisting of N—R^(9f), CH—OR^(9f),CH—NR^(9f)R^(9i) and C═CH—CO—R^(9g); A⁹ and B⁹ are independentlyselected from 5- or 6-membered rings; R^(9a), R^(9b), R^(9c) and R^(9d)are independently selected from the group consisting of H, halogen, CF₃,NO₂, NR^(9i)R^(9j), CN, COOH, (CH₂)₀₋₂—CONR^(9i)R^(9j), C₁₋₆alkyl, OH,O—C₁₋₆alkyl, O-cyclopropyl, O—(CH₂)₂—O—C₁₋₆alkyl,O—(CH₂)₂—NR^(9i)R^(9j), O—CONHR^(9i), CH₂-Z⁹-R^(9h), COR^(9i),CR^(9i)R^(9m)R^(9n), SR^(9i), SO₂R^(9o), CR^(9i)NOR^(9i),CR^(9i)NNR^(9i)R⁹j, a Q⁹-(CH₂)₂₋₉CONHOH group, furan, thiophene,pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,1,2,3-oxathiazole, 1,2,3-triazole, pyridine, pyridazine, pyrimidine,pyrazine, morpholine thiomorpholine, piperidine and pyrrolidine; R^(9e)and R^(9f) are Q^(9a)-(CH₂)₂₋₉CONHOH; R^(9g) is NH—(CH₂)₂₋₉CONHOH;R^(9h) is a (CH₂)P—R^(9k) group, wherein R^(9k) can be methyl orhydroxyl; Z⁹ is selected from the group consisting of O, NR^(9L) and S;Q⁹ is selected from the group consisting of a chemical bond, —O—, —S—,—NR^(9L)—, —NR^(9i)CO—, —CONR^(9i)—, —W⁹—, —COW⁹—, wherein W⁹ ispiperidine or pyrrolidine; Q^(9a) is a bond or a —CO—; R^(9i) and R^(9j)are independently H or a C₁₋₆alkyl; R^(9L) is H or R^(9h); R^(9m) andR^(9n) can either be a fluorine atom or oxygen atoms linked together byan alkyl chain consisting of 2 or 3 CH₂; and
 1. R^(9o) is a C₁₋₆alkyl;provided that (1) only one (CH₂)₂₋₉CONHOH is present in the molecule and(2) when X⁹ is CO and A⁹ and B⁹ are both benzene then R^(9c) and R^(9d)cannot signify Q⁹-(CH₂)₂₋₉CONHOH. 2-25. (canceled)